Transferrin receptor genes and immunogenic compositions derived therefrom

ABSTRACT

Purified and isolated nucleic acid is provided which encodes a transferrin receptor protein of a strain of Haemophilus or a fragment or an analog of the transferrin receptor protein. The nucleic acid sequence may be used to produce peptides free of contaminants derived from bacteria normally containing the Tbp1 or Tbp2 proteins for purposes of diagnostics and medical treatment. Furthermore, the nucleic acid molecule may be used in the diagnosis of infection. Also provided are recombinant Tbp1 or Tbp2 and methods for purification of the same. Live vectors expressing epitopes of transferrin receptor protein for vaccination are provided.

REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 08/337,483, filed Nov. 8, 1994, which is a continuation-in-part of application Ser. No. 08/175,116, filed Dec. 29, 1993, now abandoned; which is a continuation-in-part of application Ser. No. 08/148,968, filed Nov. 8, 1993, now abandoned.

FIELD OF INVENTION

The present invention is related to the molecular cloning of genes encoding transferring receptor and in particular to the cloning of transferrin receptor genes from Haemophilus influenzae.

BACKGROUND OF THE INVENTION

Encapsulated Haemophilus influenzae type b strains are the major cause of bacterial meningitis and other invasive infections in young children. However, the non-encapsulated or non-typable H. influenzae (NTHi) are responsible for a wide range of human diseases including otitis media, epiglottitis, pneumonia, and tracheobronchitis. Vaccines based upon H. influenzae type b capsular polysaccharide conjugated to diphtheria toxoid (Berkowitz et al., 1987. Throughout this application, various references are referred to in parenthesis to more fully describe the state of the art to which this invention pertains. Full bibliographic information for each citation is found at the end of the specification, immediately preceding the claims. The disclosures of these references are hereby incorporated by reference into the present disclosure), tetanus toxoid (Classon et al., 1989 and U.S. Pat. No. 4,496,538), or Neisseria meningitidis outer membrane protein (Black et al., 1991) have been effective in reducing H. influenzae type b-induced meningitis, but not NTHi-induced disease (Bluestone, 1982).

Otitis media is the most common illness of early childhood with 60-70% of all children of less than 2 years of age experiencing between one and three ear infections. Chronic otitis media is responsible for hearing, speech and cognitive impairments in children. H. influenzae infections account for about 30% of the cases of acute otitis media and about 60% of chronic otitis media. In the United States alone, treatment of otitis media costs between 1 and 2 billion dollars per 10 year for antibiotics and surgical procedures such as tonsillectomies, adenoidectomies and insertion of tympanostomy tubes. Furthermore, many of the causative organisms of otitis media are becoming resistant to antibiotic treatment. An effective prophylactic vaccine against otitis media is thus desirable. Non-typable strains of H. influenzae are also important pathogens responsible for pneumonia in the elderly and other individuals who are particularly susceptible to respiratory infections. There is thus a need for antigens from H. influenzae which are useful as components in immunogenic preparations that provide protection against the many serotypes of H. influenzae.

Iron is an essential nutrient Eor the growth of many bacteria. Several human pathogens, such as H. influenzae, Branhamella catarrhalis, N. meningitidis, N. gonorrhoeae and non-pathogenic commensal Neisseria strains, can utilize human transferrin as an iron source (Schryvers, 1988; Schryvers and Lee, 1989; Mickelsen and Sparling, 1981). The bacterial transferrin receptor (TfR) is composed of two chains, Tbp1 and Tbp2. In strains of H. influenzae, the molecular weight of Tbp1 is approximately 100,000, whereas the molecular weight of Tbp2 is variable, ranging from 60,000 to 90,000, depending upon the strain (Schryvers and Gray-Owen, 1992; Holland et al., 1992). Expression of H. influenzae transferrin receptor is thought to be iron-and/or hemin-regulated (Morton et al., 1993) and a putative furbinding site (Braun and Hantke, 1991) haas been identified upstream of tbp2. This sequence is found in the promoter region of genes which are negatively regulated by iron, including N. meningitidis TfR (Legrain et al., 1993). The promoter is followed by the tbp2 and tbp1 genes, an arrangement found in other bacterial TfR operons (Legrain et al, 1993; Wilton et al., 1993). Antibodies which block the access of the transferrin receptor to its iron source may prevent bacterial growth. In addition, antibodies against TfR that are opsonizing or bactericidal may also provide protection by alternative mechanisms. Thus, the transferrin receptor, fragments thereof, its constituent chains, or peptides derived therefrom are vaccine candidates to protect against H. influenzae disease. Mice immunized with N. meningitidis TfR proteins in Freund's adjuvant were protected from homologous challenge and the anti-TfR antisera were bactericidal and protective in a passive transfer assay (Danve et al., 1993). Pigs immunized with recombinant A. pleuropneumoniae Tbp2 were protected against homologous challenge but not heterologous challenge (Rossi-Campos et al., 1992). These data indicate the efficacy of TfR-based vaccines in protection from disease. It would be desirable to provide the sequence of the DNA molecule that encodes transferrin receptor and peptides corresponding to portions of the transferrin receptor and vectors containing such sequences for diagnosis, immunization and the generation of diagnostic and immunological reagents.

Poliovirus is an enterovirus, a genus of the family Picornaviridae. There are three distinct serotypes of the virus, and multiple strains within each serotype. Virulent strains are causative agents of paralytic poliomyelitis. Attenuated strains, which have reduced potential to cause paralytic disease, and inactivated virulent strains, are used as vaccines. Infection with the virus induces long-lasting, protective, mucosal immunity. Inoculation with inactivated poliovirus vaccines can also induce a mucosal immune response.

The structure of poliovirus is known, and is highly conserved among strains and serotypes. The structures of several other picornaviruses (viruses belonging to genera of the family Picornaviridae) have also been determined, and have been shown to be closely related to the structure of poliovirus. It is possible to express foreign epitopes on the capsid of polioviruses (Murdin et al, 1992) and this work has been extended to other picornaviruses. Epitopes which have been expressed are usually short, well defined, contiguous epitopes, and most have been expressed within poliovirus neutralisation antigenic site I (NAgI) or the equivalent site on other picornaviruses. This site includes the loop linking beta strands B and C (the BC loop) of poliovirus capsid protein VP1. The BC loop of VP1 is a surface-exposed loop of nine amino acids which can be replaced and extended with at least twenty-five heterologous amino acids (Murdin et al, 1991). Hybrid or chimeric polioviruses expressing transferrin receptor epitopes, which grow to a high titre and are immunogenic, would be useful as vaccines and as tools for the generation of immunological reagents.

SUMMARY OF THE INVENTION

The present invention is directed towards the provision of purified and isolated nucleic acid molecules encoding a transferrin receptor of a strain of Haemophilus or a fragment or an analog of the transferrin receptor protein. The nucleic acid molecules provided herein are useful for the specific detection of strains of Haemophilus, and for diagnosis of infection by Haemophilus. The purified and isolated nucleic acid molecules provided herein, such as DNA, are also useful for expressing the TfR genes by recombinant DNA means for providing, in an economical manner, purified and isolated transferrin receptor subunits, fragments or analogs thereof. The transferrin receptor, subunits or fragments thereof or analogs thereof, as well as nucleic acid molecules encoding the same and vectors containing such nucleic acid molecules, are useful in immunogenic compositions against diseases caused by Haemophilus, the diagnosis of infection by Haemophilus and as tools for the generation of immunological reagents. Monoclonal antibodies or mono-specific antisera (antibodies) raised against the transferrin receptor protein produced in accordance with aspects of the present invention are useful for the diagnosis of infection by Haemophilus, the specific detection of Haemophilus (in for example in vitro and in vivo assays) and for the treatment of diseases caused by Haemophilus.

Peptides corresponding to portions of the transferrin receptor or analogs thereof are useful immunogenic compositions against disease caused by Haemophilus, the diagnosis of infection by Haemophilus and as tools for the generation of immunological reagents. Monoclonal antibodies or antisera raised against these peptides, produced in accordance with aspects of the present invention, are useful for the diagnosis of infection by Haemophilus, the specific detection of Haemophilus (in, for example, in vitro and in vivo assays) and for use in passive immunization as a treatment of disease caused by Haemophilus.

In accordance with one aspect of the present invention, there is provided a purified and isolated nucleic acid molecule encoding a transferrin receptor protein of a strain of Haemophilus, more particularly, a strain of H. influenzae, specifically a strain of H. influenzae type b, such as H. influenzae type b strain DL63, Eagan or MinnA, or a non-l:ypable strain of H. influenzae, such as H. influenzae strain PAK 12085, SB33, SB12, SB29, SB30 or SB32, or a fragment or an analog of the transferrin receptor protein.

In one preferred embodiment of the invention, the nucleic acid molecule may encode only the Tbp1 protein of the Haemophilus strain or only the Tbp2 protein of the Haemophilus strain. In another preferred embodiment of the invention, the nucleic acid may encode a fragment of the transferrin receptor protein of a strain of Haemophilus having a conserved amino acid sequence which is conserved among bacteria that produce transferrin receptor protein. Such conserved amino acid sequence may have an amino acid sequence contained within the amino acid sequence of the peptides shown in Tables 2 and 3 below for Haemophilus influenzae type b strain Eagan as well as corresponding peptides of other strains of Haemophilus influenzae.

In another aspect of the present invention, there is provided a purified and isolated nucleic acid molecule having a DNA sequence selected from the group consisting of (a) any one of the DNA sequences set out in FIG. 3, 4, 5, 6, 7, 8, 9, 10 or 11 (SEQ ID NOS: 1, 2, 3, 4, 105, 108, 110, 112, 114) or the complementary DNA sequence of any one of said sequences; (b) a DNA sequence encoding one of the amino acid sequences set out in FIG. 3, 4, 5, 6, 7, 8, 9, 10 or 11 (SEQ ID NOS: 5, 6, 7, 8, 9, 10, 11, 12, 106, 107, 109, 111, 113, 115) or the complementary DNA sequence thereto; and (c) a DNA sequence which hybridizes under stringent conditions to any one of the DNA sequences defined in (a) or (b). The DNA sequence defined in (c) preferably has at least about 90% sequence identity with any one of the DNA sequences defined in (a) and (b).

In an additional aspect, the present invention includes a vector adapted for transformation of a host, comprising a nucleic acid molecule as provided herein. The vector may be one having the characteristics of plasmid DS-712-1-3 having ATCC accession number 75603 or plasmid JB-1042-7-6 having ATCC accession number 75607.

The plasmids may be adapted for expression of the encoded transferrin receptor, fragments or analogs thereof, in a heterologous or homologous host, in either a lipidated or non-lipidated form. Accordingly, a further aspect of the present invention provides an expression vector adapted for transformation of a host comprising a nucleic acid molecule as provided herein and expression means operatively coupled to the nucleic acid molecule for expression by the host of the transferrin receptor protein or the fragment or analog of the transferrin receptor protein. In specific embodiments of this aspect of the invention, the nucleic acid molecule may encode substantially all the Transferrin receptor protein, only the Tbp1 protein or only the Tbp2 protein of the Haemophilus strain. The expression means may include a nucleic acid portion encoding a leader sequence for secretion from the host of the transferrin receptor protein or the fragment or the analog of the transferrin receptor protein. The expression means also may include a nucleic acid portion encoding a lipidation signal for expression from the host of a lipidated form of the transferrin receptor protein or the fragment or the analog of the transferrin receptor protein. The expression plasmid may have the identifying characteristics of plasmid JB-1463-29, JB-1600-1 or JB1424-2-8. The host may be selected from, for example, Escherichia coli, Bacillus, Haemophilus, fungi, yeast or baculovirus and Semliki Forest virus expression systems may be used.

In an additional aspect of the invention, there is provided a transformed host containing an expression vector as provided herein. Such host may selected from JB-1476-2-1, JB-1437-4-1 and JB-1607-1-1. The invention further includes a recombinant transferrin receptor protein or fragment or analog thereof producible by the transformed host.

As described in more detail below, there has been produced Tbp1 and Tbp2 protein receptors separate from each other. Further aspects of the present invention, therefore, provide an isolated and purified Tbp1 protein of a strain of Haemophilus free from the Tbp2 protein of the Haemophilus strain and an isolated and purified Tbp2 protein of a strain of Haemophilus free from the Tbp1 protein of the Haemophilus strain. The Haemophilus strain may be H. influenzae type b or a non-typable strain of H. influenzae.

The present invention further provides synthetic peptides corresponding to portions of the transferrin receptor. Accordingly, in a further aspect of the invention, there is provided a synthetic peptide having no less than six amino acids and no more than 150 amino acids and containing an amino acid sequence corresponding to a portion only of a transferrin receptor protein of a strain of bacteria or of an analog the transferrin receptor protein. The bacterial strain preferably is a Haemophilus strain, particularly a H. influenzae strain, specifically a strain of H. influenzae type b or a non-typable strain of H. influenzae.

The peptides provided herein may conmprise an amino acid sequence which is conserved among bacteria that produce transferrin receptor protein, including strains of Haemophilus. The peptide may include an amino acid sequence LEGGFYGP (SEQ ID NO: 74) or LEGGFYG (SEQ ID NO: 85). The peptides provided herein may have an amino acid sequence selected from those presented in Table 2 or 3 below for the Eagan strain of H. influerzzae type b and corresponding amino acid sequences for other strains of H. influenzae.

In accordance with another aspect of the invention, an immunogenic composition is provided which comprises at least one active component selected from at least one nucleic acid molecule as provided herein, at least one recombinant protein as provided herein, at least one of the purified and isolated Tbp1 or Tbp2 proteins, as provided herein, at least one synthetic peptide, as provided herein, and a live vector, as provided herein, and a pharmaceutically acceptable carrier therefor or vector therefor. The at least one active component produces an immune response when administered to a host.

The immunogenic compositions provided herein may be formulated as a vaccine for in vivo administration to protect against diseases caused by bacterial pathogens that produce transferrin receptors. For such purpose, the compositions may be formulated as a microparticle, capsule or liposome preparation. Alternatively, the compositions may be provided in combination with a targeting molecule for delivery to specific cells of the immune system or to mucosal surfaces. The immunogenic composition may comprise a plurality of active components to provide protection against disease caused by a plurality of species of transferrin receptor producing bacteria. The immunogenic compositions may further comprise an adjuvant.

In accordance with another aspect of the invention, there is provided a method for inducing protection against infection or disease caused by Haemophilus or other bacteria that produce transferrin receptor protein, comprising the step of administering to a susceptible host, such as a human, an effective amount of the immunogenic composition as recited above.

In accordance with another aspect of the invention, an antiserum or antibody specific for the recombinant protein, the isolated and purified Tbp1 protein or Tbp2 protein, synthetic peptide or the immunogenic composition, is provided.

In a further aspect, there is provided a live vector for delivery of transferrin receptor to a host, comprising a vector containing the nucleic acid molecule as described above. The vector may he selected from Salmonella, BCG, adenovirus, poxvirus, vaccinia and poliovirus. The vector may specifically be poliovirus and the nucleic acid molecule may code for a fragment of transferrin receptor having an amino acid sequence of LEGGFYGP (SEQ ID NO: 74) or LEGGFYG (SEQ ID NO: 85). The present invention further includes a plasmid vector having the identifying characteristics of pT7TBP2A, pT7TBP2B, pT7TBP2C or pT7TBP2D (ATCC designation Nos. 75931, 75932, 75933, 75934).

An additional aspect of the invention provides a strain of Haemophilus that does not produce transferrin receptor protein. Such strain may comprise a gene encoding transferrin receptor which is functionally disabled, such as by insertional mutagenesis. The Haemophilus strain may be one that has been attenuated and the attenuated strain may comprise the vector for delivery of transferrin receptor.

As mentioned above, one aspect of the invention provides novel Tbp1 or Tbp2 protein of a strain of Haemophilus, preferably a strain of Haemophilus influenzae, which is isolated and purified and free from the other. A yet further aspect of the present invention provides a method for producing such proteins. Accordingly, in this yet further aspect, the present invention provides a method of producing an isolated and purified Tbp1 or Tbp2 protein of a strain of Haemophilus, comprising the steps of (a) providing a recombinant host expressing, in inclusion bodies, Tbp1 or Tbp2 protein, but not both; (b) growing the host to provide a cell mass; (c) disrupting the cell mass to provide a cell lysate; (d) fractionating the cell lysate to provide a first supernatant and a first pellet, the first supernatant comprising substantially a large proportion of soluble host proteins; (e) separating the first supernatant from the first pellet; (f) selectively extracting the first pellet to remove substantially all soluble host proteins and host membrane proteins therefrom to provide a second supernatant and an extracted pellet containing the inclusion bodies; (g) separating the second supernatant from the extracted pellet; (h) solubilizing the extracted pellet to provide a solubilized extract; and (i) fractionating the solubilized extract to provide a Tbp1 or Tbp2 protein containing fraction.

The cell lysate may be fractionated to provide the first supernatant and first pellet may be effected by at least one detergent extraction.

The solubilized extract may be fractionated by gel filtration to provide the Tbp1 or Tbp2 protein containing fraction, which may be subsequently dialyzed to remove at least the detergent and provide a further purified solution of Tbp1 or Tbp2 protein.

BRIEF DESCRIPTION OF DRAWINGS

The present invention will be further understood from the following description with reference to the drawings, in which:

FIG. 1A shows the restriction map of two plasmid clones (pBHT1 and pBHT2) of the transferrin receptor operon of Haemophilus influenzae type b strain DL63.

FIG. 1B shows the restriction map of clones S4368-3-3 and JB-901-5-3 containing TfR genes from H. influenzae type b strain Eagan.

FIG. 1C shows the restriction map of clone DS-7121-3 containing the transferrin receptor gene from H. influenzae type b strain MinnA.

FIG. 1D shows the restriction map of clone JB-1042-7-6 containing the transferrin receptor gene from the non-typable H. influenzae strain PAK 12085.

FIG. 2 illustrates the organization and restriction maps of the cloned Tbp1 and Tbp2 genes of identified strains and the genetic organization of the TfR operon with two genes (tbp1 and tbp2) in tandem forming an operon under the transcriptional regulation of a single promoter and also depicts the 3.0 kb DNA fragment of pBHIT2 used to probe libraries for TfR genes from the Haemophilus strains.

FIGS. 3A-3Q show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 1) and their deduced amino acid sequences (SEQ ID NO: 5-Tbp1 and SEQ ID NO: 6-Tbp2) from H. influenzae type b, strain DL63. The underlined amino acid sequences correspond to peptides of Tbp1 identified by amino acid sequencing. The putative signal sequences are indicated by double overlining and correspond to residues 1 to 17 for Tbp1 and 1 to 25 for Tbp2.

FIGS. 4A-4Q show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 2) and their deduced amino acid sequences (SEQ ID NO: 7-Tbp1 and SEQ ID NO: 8-Tbp2) from H. influenzae type b strain Eagan. Putative-35, -10 and ribosomal binding site sequences are overlined.

FIGS. 5A-5Q show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 3) and their deduced amino acid sequences (SEQ ID NO: 9-Tbp1 and SEQ ID NO: 10-Tbp2) from H. influenzae type b strain MinnA. Putative-35, -10 and ribosomal binding site sequences are overlined.

FIGS. 6A-6Q show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 4) and their deduced amino acid sequences (SEQ ID NO. 11-Tbp1 and SEQ ID NO. 12-Tbp2) from the non-typable H. influenzae strain PAK 12085. Putative-35, -10) and ribosomal binding site sequences are overlined.

FIGS. 7A-7N show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 105) and their deduced amino acid sequences (SEQ ID NO. 106-Tbp1 and SEQ ID NO. 107-Tbp2) from the non-typable H. influenzae strain SB33.

FIGS. 8A-8G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO: 108) and the deduced amino acid sequence (SEQ ID NO: 109-Tbp2) from non-typable strain H. inffluenzae strain SB12.

FIGS. 9A-9G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO: 110) and the deduced amino acid sequence (SEQ ID NO: 111-Tbp2) from non-typable strain H. influenzae strain SB29.

FIGS. 10A-10G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO: 112) and the deduced amino acid sequence (SEQ ID NO: 113-Tbp2) from non-typable strain H. influenzae strain SB30.

FIGS. 11A-11G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO: 114) and the deduced amino acid sequence (SEQ ID NO: 115-Tbp2) from non-typable strain H. influenzae strain SB32.

FIG. 12A shows the nucleotide sequences of the promoter regions and 5'-end of the tbp2 genes from H. influenzae strains Eagan (SEQ ID NO: 116), MinnA (SEQ ID NO: 117), PAK 12085 (SEQ ID NO: 118) and SB33 (SEQ ID NO: 119). The coding strand primer used to amplify tbp2 genes by PCR is underlined (SEQ ID NO: 120).

FIG. 12B shows the nucleotide sequence of the intergenic region and 5'-end of the tbp1 genes from H. influenzae strains Eagan (SEQ ID NO: 121), MinnA (SEQ ID NO: 122), DL63 (SEQ ID NO: 123), PAK 12085 (SEQ ID NO: 124), SB12 (SEQ ID NO: 125), SB29 (SEQ ID NO: 126), SB30 (SEQ ID NO: 127), and SB32 (SEQ ID NO: 128). The non-coding strand primer used to amplify the tbp2 genes by PCR is underlined (SEQ ID NO: 129).

FIG. 13 shows the agarose gel analysis of PCR amplified tbp2 genes from non-typable H. influenzae strains SB12, SB29, SB30, SB32 and SB33. Lane 1 is SB33, lane 2 is SB12, lane 3 is SB29, lane 4 is SB30, lane 5 is SB32.

FIGS. 14A-14C show a comparison of the amino acid sequences of Tbp1 from H. influenzae strains Eagan, DL63, PAK 12085 and SB33 (SEQ ID NOS: 7, 5, 11 and 106), N. meningitidis strains B16B6 and M982 (SEQ ID NOS: 94 and 95), and N. gonorrhoeae strain FA19 (SEQ ID NO: 96).

FIGS. 15A-15D show a comparison of the amino acid sequence of Tbp2 from H. influenzae strains Eagan, DL63, PAK 12085, SB12, SB29, SB30 and SB32 (SEQ ID NOS: 8, 6, 12, 109, 110, 112, 114), N. meningitidis, strains B16B6 and M982 (SEQ ID NOS: 97 and 98), N. gonorrhoeae strain FA19, and Actinobacillus pleuropneumoniae strains AP205 and AP37 (SEQ ID NOS: 99 and 100).

FIGS. 16A' and 16A" show the predicted secondary structure of H. influenzae Tbp1 protein and FIGS. 16B' and 16B" show the predicted secondary structure of H. influenzae Tbp2 protein.

FIG. 17 shows the construction scheme of plasmid JB-1468-29 which expresses H. influenzae type b Eagan Tbp1 from E. coli.

FIG. 18 shows the construction scheme of plasmid JB-1424-2-8 which expresses H. influenzae type b Eagan Tbp2 from E. coli.

FIG. 19 shows the oligonucleotide pairs (SEQ ID NOS: 130, 131) used to construct plasmid JB-1424-2-8.

FIGS. 20A-20B show the sequence of oligonucleotide pairs A (SEQ ID NOS: 86, 87), B (SEQ ID NOS: 88, 89), C (SEQ ID NOS: 90, 91) and D (SEQ ID NOS: 92, 93) for constructing Tbp1 and Tbp2 expression plasmids.

FIG. 21 shows the construction scheme of plasmid JB-1600-1 which expresses H. influenzae strain SB12 Tbp2 from E. coli.

FIG. 22 shows SDS-PAGE gels of products from the expression of Haemophilus type b Eagan Tbp1 protein, Eagan Tbp2 protein, and non-typable H. influenzaea SB12 Tbp2 protein from E. coli. Lane 1, JB-1476-2-1 (T7/Eagan Tbp1) at t_(o) ; lane 2, JB-1476-2-1 at t=4h induction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) at t_(o) ; lane 5, JB-1437-4-1 at t=4h induction; lane 6, JB-1607-1-1 (T7/SB12 Tbp2) at t_(o) ; lane 7, JB-1607-1-1 at t=4h induction.

FIG. 23 shows a purification scheme for recombinant Tbp1 and Tbp2 expressed from E. coli.

FIG. 24, comprising Panel A and B, shows an analysis of the purity of recombinant Tbp1 (Panel A) and Tbp2 (Panel B) purified by the scheme of FIG. 23. Lane 1 contains molecular weight size markers (106, 80, 49.5, 32.5, 27.5 and 18.5 kDa), Lane 2 is E. coli whole cell lysate. Lane 3 is solubilized inclusion bodies. Lane 4 is purified Tbp1 or Tbp2.

FIGS. 25A and 25B show the immunogenicity of rTbp1 (upper panel) and rTbp2 (lower panel) in mice.

FIG. 26 shows the reactivity of anti-Eagan rTbp1 antisera with various H. influenzae strains on a Western blot. Lane 1, BL21/DE3; lane 2, SB12-EDDA; lane 3, SB12 +EDDA; lane 4, SB29 -EDDA; lane 5, SB29 +EDDA; lane 6, SB33 -EDDA; lane 7, SB33 +EDDA; lane 8, Eagan -EDDA; lane 9, Eagan +EDDA; lane 10, B. catarrhalis 4223 -EDDA; lane 11, B. catarrhalis 4223 +EDDA; lane 12, N. meningitidis 608 -EDDA; lane 13, N. meningitidis 608 +EDDA; lane 14, induced JB-1476-2-1 expressing recombinant Eagan Tbp1; lane 15, molecular weight markers. Specific ˜95 kDa bands reacted with the anti-Tbp1 antisera in lanes 3, 4, 5, 7, 8 and 9, corresponding to H. influenzae strains SE12, SB29, SB33 and Eagan; ˜110 kDa bands in lanes 10 and 11, corresponding to B. catarrhalis strain 4223; and ˜80 kDa bands in lanes 12 and 13, corresponding to N. meningitidis 608.

FIG. 27 shows the reactivity of anti-Eagan rTbp2 antisera with various H. influenzae strains on a Western blots. Lane 1, molecular weight markers; lane 2, induced JB-1437-4-1 expressing recombinant Eagan Tbp2; lane 3, SB12-EDDA; lane 4, SB12 +EDDA; lane 5, SB29 -EDDA; lane 6, SB29 +EDDA; lane 7, SB30 -EDDA; lane 8, SB30 +EDDA; lane 9, SB32 -EDDA; lane 10, SB33-EDDA; lane 11, SB33 +EDDA; lane 12, PAK -EDDA; lane 13, PAK +EDDA; lane 14, Eagan -EDDA; lane 15, Eagan +EDDA. SpeciEic bands of 60-70 kDa were reactive with the anti-Tbp2 antisera in lanes, 3, 6, 7, 8, 13, 14 and 15, i.e. strains SB12, SB29, SB30, PAK and Eagan.

FIG. 28 shows the construction of plasmids pUHIT1KFH and pUHIT1KFP used to generate strains of H. influenzae that do not produce transferrin receptor.

FIG. 29 shows the construction of plasmids encoding chimeric polioviruses expressing an epitope derived from transferrin receptor protein that is conserved among bacteria that produce transferrin receptor protein.

FIG. 30, comprising Panels A, B and C, is a Western blot showing the reactivity of antisera produced by immunization of rabbits with poliovirus chimeras expressing an epitope derived from transferrin receptor protein that is conserved among bacteria that produce transferrin receptor protein. Panel A shows a Coomassie Brilliant Blue-stained gel showing purified recombinant Tbp2 from H. influenzae strain SB12 expressed in E. coli (lane 1), purified Tbp2 from Branhamella catarrhalis strain 4223 (lane 2), a whole cell lysate of iron-limited B. catarrhalis strain 4223 (lane 3), a whole cell lysate of E. coli JM109 grown under non-iron limited conditions (lane 5). Panel B shows results of a Western blot of a replicate gel using a pool of the sera collected on day 27 from rabbits immunised with PV1TBP2A (rabbits 40, 41 and 42). Panel C shows the results for a pool of prebleed sera from the same, which displayed minimal specific reactivity.

In some of the above Figures, the following abbreviations have been used to designate particular site specific restriction endonucleases: R, Eco RI; Ps, Pst I; H, Hind III; Bg, Bgl II; Nde, Nde I; Ear, Ear I; and Sau, Sau3A I.

In FIG. 28, the following abbreviations have been used to designate particular site specific restriction endonucleases: A, Acc I; B Bam HI; E, Eco RI; O, Xho I; H, Hind III; Ps, Pst I; V, Eco RV; X, Xba I, G, Bgl II; S, Sal I; K, Kpn I; and S*, Sac I.

GENERAL DESCRIPTION OF THE INVENTION

Any Haemophilus strain may be conveniently used to provide the purified and isolated nucleic acid which may be in the form of DNA molecules, comprising at least a portion of the nucleic acid coding for a transferrin receptor as typified by embodiments of the present invention. Such strains are generally available from clinical sources and from bacterial culture collections, such as the American Type Culture Collection.

According to an aspect of the invention, the transferrin receptor protein may be isolated from Haemophilus strains by the methods described by Schryvers (1989), Ogunnaviwo and Schryvers (1992) and U.S. Pat. No. 5,141,743, the subject matter of which is hereby incorporated by reference. Although the details of an appropriate process are provided in patent U.S. Pat. No. 5,141,743, a brief summary of such process is as follows. Isolation of transferrin receptor is achieved by isolating a membrane fraction from a bacterial strain expressing transferrin binding activity and purifying the transferrin receptor by an affinity method involving the sequential steps of prebinding of transferrin to the transferrin receptor in the membrane fraction, solubilising the membrane, immobilising the transferrin and separating the transferrin receptor from the immobilised transferrin. Alternatively, the receptor proteins may be isolated by a modification of the above method in which the prebinding step is avoided and a high concentration of salt is included in the solubilization buffer to allow direct isolation with immobilized transferrin as described in Ogunnariwo and Schryvers (1992).

In this application, the term "transferrin receptor" is used to define a family of Tbp1 and/or Tbp2 proteins which includes those having variations in their amino acid sequences including those naturally occurring in various strains of, for example, Haemophilus. Other bacterial sources of transferrin receptor include, but are not limited to, species of Neisseria, Branhamella, Pasteurella and Actinobacillus. Some, if not all, of these bacteria contain both Tbp1 and Tbp2. The purified and isolated DNA molecules comprising at least a portion coding for transferrin receptor of the present invention also include those encoding functional analogs of transferrin receptor. In this application, a first protein or peptide is a "functional analog" of a second protein if the first protein is immunologically related to and/or has the same function as the second protein or peptide. The functional analog may be, for example, a fragment of the protein or a substitution, addition or deletion mutant thereof.

In one particular embodiment, the transferrin receptor was isolated from H. influenzae type b strain DL63 and purified by affinity chromatography methods, as described by Schryvers (1989), Ogunnariwo and Schryvers (1992) and in U.S. Pat. No. 5,141,743. The isolated and purified transferrin receptor was used to generate anti-TfR antisera in rabbits. Chromosomal DNA from H. influenzae type b strain DL63 was mechanically sheared, EcoRI linkers added, and a λZAP expression library constructed. The library was screened with the anti-TfR rabbit antisera and two positive clones (pBHIT1 and pBHIT2) were obtained which had overlapping restriction maps (FIG. 1A and FIG. 2). The clones were sequenced and two large open reading frames were identified (FIG. 2). The nucleotide sequences of the transferrin receptor genes Tbp1 and Tbp2 (SEQ ID NO: 1) frown H. influenzae DL63 and their deduced amino acid sequences (SEQ ID NO: 5-Tbp1 and SEQ ID NO: 6-Tbp2) are shown in FIG. 3. The sequence analysis showed the TfR operon to consist of two genes (Tbp1 and Tbp2) arranged in tandem and transcribed from a single promoter (as particularly shown in FIG. 2 and FIG. 3). The Tbp2 protein tends to vary in molecular weight depending on the species whereas the Tbp1 protein tends to have a more consistent molecular weight with some variability across the various bacteria which have TfR genes. The molecular weight of Tbp1 is usually in the range of 94 to 106,000 whereas the molecular weight of Tbp2 varies considerably from 58 to 98 000.

Amino acid sequencing of the N-termini and cyanogen bromide fragments of transferrin receptor from H. influenzae DL63 was performed. The N-terminus of Tbp2 was blocked but amino acid sequences were identified by sequencing of Tbp1 and are indicated by underlining within the protein sequence of FIG. 3. These peptide sequences are Glu Thr Gln Ser lle Lys Asp Thr Lys Glu Ala lle Ser Ser Glu Val Asp Thr (as shown in FIG. 3, SEQ ID NO: 101) and Leu Gln Leu Asn Leu Glu Lys Lys lle Gln Gln Asn Trp Leu Thr His Gln lle Ala Phe (as shown in FIG. 3; SEQ ID NO: 102). The signal sequence of Tbp1 and the putative signal sequence of Tbp2 are indicated by double overligning in FIG. 3. The putative signal sequence for Tbp1 is Met Thr Lys Lys Pro Tyr Phe Arg Leu Ser Ile Ile Ser Cys Leu Leu Ile Ser Cys Tyr Val Lys Ala (SEQ ID NO: 103). The putative signal sequence for Tbp2 is Met Lys Ser Val Pro Leu Ile Ser Gly Gly Leu Ser Phe Leu Leu Ser Ala (SEQ ID NO: 104). The derived amino acid sequence of the N-terminal region of Tbp2 indicates that it is a lipoprotein.

Chromosomal DNA from H. influenzae type b strain Eagan was prepared and libraries were generated. The first library was constructed from DNA partially digested with Sau3A I, size-fractionated for ˜5-10 kb fragments, and cloned into a pUC-based plasmid. The second library was constructed from Eco RI-restricted chromosomal DNA fragments cloned into λZAP. Both libraries were probed with a 5'-fragment of the pBHIT clone as shown in FIG. 2 and partial clones of the TfR genes of H. influenzae Eagan termed S-4368-3-3 and JB-901-5-3 were obtained. Thus, referring to FIGS. 1B and 2, there is illustrated according to further aspects of the present invention, plasmid clones S-4368-3-3 and JB-901-5-3 encoding Tbp1 and Tbp2 from H. influenzae type b strain Eagan. The DNA sequences of the Tbp1 and Tbp2 genes (SEQ ID NO: 2) from H. influenzae type b strain Eagan and their deduced amino acid sequences (SEQ ID NOS: 7 and 8) are shown in FIG. 4 with the Tbp2 sequence being the first gene in the operon. In FIG. 4, putative-35, -10 and ribosomal binding site sequences are overlined.

Chromosomal DNA from H. influenzae type b strain MinnA was prepared and the DNA partially digested with Sau3A I, size-fractionated for 10-20 kb fragments, and cloned into the BamHI site of EMBL3. The library was probed with the 5'-fragment of the pBHIT clone (FIG. 2) and a full-length clone encoding TfR (DS-712-1-3) was obtained. Referring to FIGS. 1C and 2, there is illustrated according to additional aspects of the present invention, plasmid clone DS 712-1-3 encoding Tbp1 and Tbp2 from H. influenzae type b strain Minna. The DNA sequences of Tbp1 and Tbp2 (SEQ ID NO: 3) and their deduced amino acid sequences (SEQ ID NO: 9-Tbp1 and SEQ ID NO: 10-Tbp2) from H. influenzae type b strain MinnA are shown in FIG. 5 where the Tbp2 sequence is first in the operon. In FIG. 5, Putative-35, -10 and ribosomal binding site sequences are overlined.

Chromosomal DNA from the non-typable H. influenzae strain PAK 12085 was prepared. The DNA was partially digested with Sau3A I, size-fractionated for 10-20 kb fragments, and cloned into the BamH I sites of EMBL3. The library was probed with the fragments of the pBHIT clone (FIG. 2) and a full-length clone encoding TfR (JB-1042-7-6) was obtained. The restriction map of clone JB-1042-7-6 is shown in FIGS. 1D and 2 and the nucleotide sequences of the Tbp1 and Tbp2 genes (SEC ID NO: 4) from H. influenzae PAK 12085 and their deduced amino acid sequences are shown in FIG. 6 (SEQ ID NOS: 11, 12), with the Tbp2 sequence first. In FIG. 6, Putative-35,-10 and ribosomal binding site sequences are overlined.

Chromosomal DNA from the otitis-media derived non-typable H. influenzae strain SB33 was prepared. The DNA was partially digested with Sau3A I, size-fractionated for 10-20 kb fragments, and cloned into the BamH I site of EMBL3. The library was probed with the fragments of the pBHIT clone (FIG. 2) and a full-length clone encoding TfR (JB-1031-2-9) was obtained. The restriction map of clone JB-1031-2-9 is shown in FIG. 2 and the nucleotide sequences of the Tbp1 and Tbp2 genes (SEQ ID NO: 4) from H. influenzae SB33 and their deduced amino acid sequences are shown in FIG. 7 (SEQ ID NOS: 11, 12), with the Tbp2 sequence first. The SB33 tbp2 gene was found to have a single base deletion which resulted in a frame-shift at residue 126 and premature truncation of the resulting protein at residue 168.

PCR amplification of the tbp2 genes from otitis media-derived NTHi strains SB12, SB29, SB30 and SB32 was performed and the genes sequenced.

The nucleotide sequence of the tbp2 genes from non-typable H. influenzae strains SB12 (SEQ ID NO: 105), SB29 (SEQ ID NO: 108), SB30 (SEQ ID NO: 110) and SB32 (SEQ ID NO: 112) are shown in FIGS. 8, 9, 10 and 11 respectively.

All of the amplified tbp2 genes were found to encode full-length Tbp2 proteins indicating that the defective tbp2 gene of strain SB33 was atypical.

The three H. influenzae b strains all had identical short intergenic sequences of only 13 bp between tbp2 and tbp1, but the NTHi strains PAK 12085 and SB33 had longer intergenic sequences of 27 bp (FIG. 12).

Strain SB12 had a 13 bp intergenic sequence identical to that found in the H. influenzae b strains while strains SB29, SB30 and SB32 contained longer intergenic sequences (27-30 bp) as found in the other NTHi strains PAK 12085 and SB33 (FIG. 2B). All nine strains have a common core conserved 13 bp sequence between their tbp2 and tbp1 genes.

A pentapeptide sequence near the amino terminus of H. influenzae Tbp1 was identified (FIG. 12) which is similar to the TonB box. The tonB gene of H. influenzae has been recently cloned and sequenced (Jarosik et al., 1994).

The amino acid sequences of Tbp1 from H. influenzae strains Eagan/MinnA, DL63, PAK 12085 and SB33 strains are compared in FIG. 14. The Tbp1 proteins of Eagan and MinnA are identical and 912 amino acids in length, that of DL63 has 914 residues, that of PAK 12085 has 914 residues, and that of SB33 has 911 residues. The H. influenzae Tbp1 proteins are highly conserved with 95-100% sequence identity. The amino acid sequences of Tbp2 from H. influenzae strains Eagan/MinnA, DL63, PAK 12085 SB12, SB29, SB30 and SB32 are compared in FIG. 15. The Tbp2 proteins of Eagan and MinnA are identical and contain 660 amino acids, that of DL63 has 644 residues, and that of PAK 12085 has 654 residues. There is a single base deletion in the SB33 tbp2 gene which results in a frame-shift at residue 126 and premature trunction of the resulting protein at residue 108. The missing base was confirmed by direct sequencing of PCR amplified chromosomal DNA. With the exception of Eagan and MinnA which are identical, the Tbp2 protein sequences are less conserved with only 66-70% identity, but there are several short segments of conserved sequence which can be identified in FIG. 15. The PCR amplified tbp2 genes from strains SB12, SB29, SB30 and SB32 were all found to encode full-length Tbp2 proteins. There was sequence and size heterogeneity amongst the deduced Tbp2 proteins wherein SB12 had 648 amino acids, SB29 had 631 residues, SB30 had 630 residues and SB32 had 631 residues.

Putative secondary structures of Eagan Tbp1 and Tbp2 were determined (FIGS. 16A and 16B). Both proteins have several transmembrane domains, with Tbp1 traversing the membrane 20 times and Tbp2 crossing it 12 times. Three exposed conserved epitopes were identified in the Tbp1 amino-terminal region (DNEVTGLGK-SEQ ID NO: 43, EQVLN/DIRDLTRYD-SEQ ID NOS: 139 and 140, and GAINEIEYENVKAVEISK-SEQ ID NO: 141) and one in the C-terminal region (GI/VYNLF/LNYRYVTWE-SEQ ID NOS: 142 and 143). Only three small conserved regions can be identified within the Tbp2 proteins of the human pathogens: CS/LGGG(G)SFD-SEQ ID NOS: 75, 144 and 145 at the N-terminal, LE/SGGFY/FGP-SEQ ID NOS: 74 and 146 located internally, and VVFGAR/K-SEQ ID NOS: 83 and 84 at the C-terminus

The discovery that the Tbp2 amino acid sequence varies between strains of Haemophilus alllows for the grouping of Haemophilus into sub-groups defined by the same Tbp2 amino acid sequence. This discovery allows the rational selection of a minimal number of Tbp1 and/or Tbp2 sequences or synthetic peptides representing epitopes shared by such subtypes within strains of Haemophilus to be used in immunogenic compositions for, for example, immunization against the diseases caused by Haemophilus and other bacteria that produce transferrin receptor with sequence similarities to Tbp1 and Tbp2 from Haemophilus species. Thus, a minimal number of transferrin receptor, analogs, fragments, and/or peptides, may be used to immunize against many or all strains of Haemophilus and other bacterial pathogens that produce transferrin receptor.

Furthermore, the amino acid sequences of the transferrin receptor from a range of bacterial pathogens (H. influenzae type b, non-typable H. influenzae, Neisseria meningitidis, Neisseria gonorrhoeae and Actinobacillus (Haemophilus) pleuropneumoniae) were compared as shown in FIGS. 14 and 15. This analysis revealed regions of Tbp1 and Tbp2 which are conserved between all of these bacteria. Some of such conserved sequences are contained in peptides in Tables 2 and 3. In particular the sequences DNEVTGLGK (SEQ ID: 43), EQVLNIRDLTRYDPGI (SEQ ID NO: 44), EQVLNIRDLTRYDPGISVVEQG RGASSGYSIRGMD (SEQ ID NO: 45), GAINEIEYENVKAVEISKG (SEQ ID NO: 46) and GALAGSV (SEQ ID NO: 47) are conserved in Tbp1 (Table 1 and FIG. 14). Particular conserved sequences in Tbp2 include LEGGFYGP (SEQ ID NO: 74), CSGGGSFD (SEQ ID NO: 75), YVYSGL (SEQ ID NO: 76), CCSNLSYVKFG (SEQ ID NO: 77), FLLGHRT (SEQ ID NO: 78), EFNVOF (SEQ ID NO: 79), NAFTGTA (SEQ ID NO: 80), VNGAFYG (SEQ ID NO: 81), ELGGYF (SEQ ID NO: 82), VVFGAIZ (SEQ ID NO: 83) and VVFGAK (SEQ ID NO: 84) (Table 2 and FIG. 15).

The discovery of conserved sequences within the transferrin receptor of a range of bacterial pathogens allows the selection of a minimal number of antigens having particular amino acid sequences (including in the form of synthetic peptides) to immunize against the disease caused by pathogens that have transferrin receptors. Such bacteria in addition to those recited above include other species of Neisseria, such as Neisseria gonorrhoeae, and Branhamella, including Branhamella catarrhalis. Such conserved amino acid sequences among many bacterial pathogens permits the generation of TfR specific antibodies, including monoclonal antibodies, that recognize most if not all transferrin receptors. Antiserum was raised against peptides corresponding to conserved portions of the transferrin receptor. This antiserum recognized the transferrin receptor in Branhamella catarrhalis. Such antisera are useful for the detection and neutralization of most if not all bacteria that produce TfR protein and are also useful for passive immunization against the diseases caused by such pathogens. Diagnostic assays and kits using such conserved amino acid sequences are useful to detect many if not all bacteria that produce transferrin receptor.

Epitopes containing the afore-mentioned amino acid sequences can be delivered to cells of the immune system by the use of synthetic peptides containing such sequences, or by the use of live vectors expressing such sequences, or by the direct administration of nucleic acid molecules encoding the amino acid sequence.

Some peptides containing conserved amino acid sequences within the Tbp1 proteins of H. influenzae type b strains Eagan, MinnA, DL63 and the nontypable strain PAK 12085 are shown in Table 2. Antibodies to some of these peptides were raised in guinea pigs (Table 4). Peptides containing conserved amino acid sequences within the Tbp2 proteins of H. influenzae type b strains Eagan, Minn A, DL63 and the nontypable strain PAK 12085 are shown in Table 3. Antibodies to some of these peptides were raised in guinea pigs (Table 4).

The coding sequences of the Tbp1 and Tbp2 genes may be cloned into appropriate expression vectors to produce recombinant proteins. Recombinant Tbp1 and Tbp2 were expressed from E. coli using the T7 expression system. The tbp1 gene encoding the mature Eagan Tbp1 protein was cloned in-frame behind the T7 promoter generating plasmid JB-1468-29, as shown in FIG. 17. When introduced into BL21/DE3 cells and induced with IPTG or lactose, Eagan Tbp1 protein was expressed as shown in FIG. 22.

The tbp2 gene encoding the mature Tbp2 protein was cloned in-frame behind the T7 promotor generating plasmid JB-1424-2-8 as shown in FIG. 18. When introduced into E. coli cells and induced as above, Tbp2 protein was expressed as shown in FIG. 22.

The tbp2 gene from strain NTHi SB12 was amplified by PCR. The resultant amplified DNA contains the authentic H. influenzae Tbp2 signal sequence before the mature protein. The SB12 tbp2 gene encoding the signal sequence and the mature protein was cloned into the pT7-7 expression system as shown in FIG. 21. When the resultant plasmid (JB-1600-1) was introduced into E. coli BL21/DE3 cells and induced, SB12 Tbp2 was expressed, as shown in FIG. 22.

Recombinant proteins Tbp1 and Tbp2 produced in E. coli as inclusion bodies were purified by the scheme shown in FIG. 23. The purified proteins were at least about 70% pure as shown in FIG. 24. Immunogenicity studies were performed in mice with the purified recombinant Tbp1 and Tbp2 proteins. Both proteins elicited a good immune response in mice at 3-10 μg doses (FIG. 25).

Antisera raised to recombinant Tbp1 or Tbp2 derived from one H. influenzae strain are cross-reactive with other strains, making these potentially useful diagnostic reagents (FIGS. 26 and 27).

Plasmids pUHIT1KFH and pUHITKFP shown in FIG. 28, contain a selectable antibiotic resistance marker cloned within the transferrin receptor operon and were constructed to insertionally inactivate the transferrin receptor operon. These plasmids were used to transform Haemophilus to generate strains that do not produce transferrin receptor Tbp1 and/or Tbp2 as described in Example 19. Such strains are useful as negative controls (since they do not produce TfR) in in vitro and in vivo detection and diagnostic embodiments. Such strains are also expected to be attenuated for in vivo growth and are useful as live vaccines to provide protection against diseases caused by Haemophilus.

As discussed above, epitopes of transferrin receptor proteins can be delivered to cells of the immune system by the use of live vectors expressing such amino acid sequences and the live vector may be poliovirus. Referring to FIG. 29 there is illustrated the construction of hybrid polioviruses expressing an epitope of transferrin receptor protein including the conserved epitope from Tbp2 LEGGFYGP (SEQ ID NO: 74). Such viruses were recognized by antibodies raised against a peptide incorporating the amino acid sequence LEGGFYGP (SEQ ID NO: 74) (Table 5) indicating that the viruses expressed this sequence in an antigenically recognisable form. PV1TBP2A and PV1TBP2B were also neutralized by rabbit antisera raised against H. influenzae strain DL63 tbp2, indicating that at least these two viruses expressed the sequence in a form recognisable to antibodies raised against the protein. All viruses were neutralisable by anti-PV1 sera, indicating that the changes in polio neutralization antigenic site I had not significantly affected other antigenic sites on the viruses. Furthermore, rabbit antiserum produced by immunization with poliovirus chimera PV1TBP2A or PV1TBP2B recognized a peptide incorporating the amino acid sequence LEGGFYGP (SEQ ID NO: 74). This indicates that the sequences expressed by PV1TB2A and PV1TBP2B are immunogenic and elicit antibodies capable of recognizing the same sequence in the context of a synthetic peptide.

Referring to FIG. 30, panel A shows an SDS PAGE gel showing purified recombinant tbp2 from H. influenzae strain SB12 expressed in E. coli (lane 1), tbp2 from Branhamella catarrhalis strain 4223 (lane 2), a whole cell lysate of iron-limited B. catarrhalis strain 4223 (land 3), a whole cell lysate of iron-limited E. coli JM109 (lane 4), and a whole cell lysate of E. coli JM109 grown under non-iron limited conditions (lane 5). Panel B shows results of a Western blot of a replicate gel using a pool of sera from rabbits immunized with PV1TBP2A. There was a strong reaction with the purified transferrin-binding proteins in lanes 1 and 2, and with a similar sized band in lane 3. There was no significant reaction with any E. coli proteins (lanes 4 and 5). Panel C shows the results for a pool of prebleed sera from the same rabbits, which displayed minimal specific reactivity. These results show that PV1TBP2A is able to induce antisera specific for transferrin binding proteins from H. influenzae and B. catarrhalis, and that the antisera can distinguish B. catarrhalis from E. coli, which does not express an equivalent protein.

The purified and isolated DNA molecules comprising at least a portion coding for a transferrin receptor of a species of Haemophilus typified by the embodiments described herein are advantageous as:

nucleic acid probes for the specific identification of Haemophilus strains in vitro or in vivo.

the products encoded by the DNA molecules are useful as diagnostic reagents, antigens for the production of Haemophilus-specific antisera, for vaccination against the diseases caused by species of Haemophilus and (for example) detecting infection by Haemophilus.

peptides corresponding to portions of the transferrin receptor as typified by the embodiments described herein are advantageous as diagnostic reagents, antigens for the production of Haemophilus-specific antisera, for vaccination against the diseases caused by species of Haemophilus and (for example) for detecting infection by Haemophilus.

The transferrin receptor encoded by the nucleic acid molecules of the present invention, fragments and analogs thereof, and peptides containing sequences corresponding to portions of the transferrin receptor that are conserved between various isolates of Haemophilus and other bacteria that produce transferrin receptor, are useful in diagnosis of and immunization against diseases caused by any bacterial strain that produces transferrin receptor. In particular, peptides containing the sequences LEGGFYGP are conserved in the transferrin receptor proteins of many bacterial pathogens that produce transferrin receptor and are appropriate for diagnosis of and immunization against diseases caused by bacteria that produce transferrin receptor. Such bacteria include but are not limited to species of Haemophilus, Neisseria (including N. meningitidis and N. gonorrhoeae) and Branhamella (including B. catarrhalis).

It is clearly apparent to one skilled in the art, that the various embodiments of the present invention have many applications in the fields of vaccination, diagnosis, treatment of, for example, Haemophilus infections, and infections with other bacterial pathogens that produce transferrin receptor and the generation of immunological reagents. A further non-limiting discussion of such uses is further presented below.

1. Vaccine Preparation and Use

Immunogenic compositions, suitable to be used as vaccines, may be prepared from immunogenic transferrin receptor, analogs and fragments thereof and/or peptides as disclosed herein. The vaccine elicits an immune response which produces antibodies, including anti-transferrin receptor antibodies and antibodies that are opsonizing or bactericidal. Should the vaccinated subject be challenged by Haemophilus or other bacteria that produce a transferrin receptor, the antibodies bind to the transferrin receptor and thereby prevent access of the bacteria to an iron source which is required for viability. Furthermore, opsonizing or bactericidal anti-TfR antibodies may also provide protection by alternative mechanisms.

Vaccines containing peptides are generally well known in the art, as exemplified by U.S. Pat. Nos. 4,601,903; 4,599,231; 4,599,230; and 4,596,792; all of which references are incorporated herein by reference. Immunogenic compositions including vaccines may be prepared as injectables, as liquid solutions or emulsions. The transferrin receptor, analogs and fragments thereof and/or peptides may be mixed with pharmaceutically acceptable excipients which are compatible with the transferrin receptor, fragments analogs or peptides. Such excipients may include, water, saline, dextrose, glycerol, ethanol, and combinations thereof. The immunogenic compositions and vaccines may further contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or adjuvants to enhance the effectiveness of the vaccines. Immunogenic compositions and vaccines may be administered parenterally, by injection subcutaneously or intramuscularly. Alternatively, the immunogenic compositions formed according to the present invention, may be formulated and delivered in a manner to evoke an immune response at mucosal surfaces. Thus, the immunogenic composition may be administered to mucosal surfaces by, for example, the nasal or oral (intragastric) routes. The immunogenic composition may be provided in combination with a targeting molecule for delivery to specific cells of the immune system or to mucosal surfaces. Some such targeting molecules include strain B12 and fragments of bacterial toxins, as described in WO 92/17167 (Biotech Australia Pty. Ltd.), and monoclonal antibodies, as described in U.S. Pat. No. 5,194,254 (Barber et al). Alternatively, other modes of administration including suppositories and oral formulations may be desirable. For suppositories, binders and carriers may include, for example, polyalkalene glycols or triglycerides. Oral formulations may include normally employed incipients such as, for example, pharmaceutical grades of saccharine, cellulose and magnesium carbonate. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain 10-95% of the transferrin receptor, fragment analogs and/or peptides.

The vaccines are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective, protective and immunogenic. The quantity to be administered depends on the subject to be treated, including, for example, the capacity of the individual's immune system to synthesize antibodies, and if needed, to produce a cell-mediated immune response. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner. However, suitable dosage ranges are readily determinable by one skilled in the art and may be of the order of micrograms of the transferrin receptor, analogs and fragments thereof and/or peptides. Suitable regimes for initial administration and booster doses are also variable, but may include an initial administration followed by subsequent administrations. The dosage of the vaccine may also depend on the route of administration and will vary according to the size of the host.

The nucleic acid molecules encoding the transferrin receptor of the present invention may also be used directly for immunization by administration of the DNA directly, for example by injection for genetic immunization or by constructing a live vector such as Salmonella, BCG, adenovirus, poxvirus, vaccinia or poliovirus. A discussion of some live vectors that have been used to carry heterologous antigens to the immune system are discussed in for example O'Hagan (1992). Processes for the direct injection of DNA into test subjects for genetic immunization are described in, for example, Ulmer et al., 1993.

The use of peptides in vivo may first require their chemical modification since the peptides themselves may not have a sufficiently long serum and/or tissue half-life and/or sufficient immunogenicity. Such chemically modified peptides are referred to herein as "peptide analogs". The term "peptide analog" extends to any functional chemical equivalent of a peptide characterized by its increased stability and/or efficacy and immunogenicity in vivo or in vitro in respect of the practice of the invention. The term "peptide analog" is also used herein to extend to any amino acid derivative of the peptides as described herein. Peptide analogs contemplated herein are produced by procedures that include, but are not limited to, modifications to side chains, incorporation of unnatural amino acids and/or their derivatives during peptide synthesis and the use of cross-linkers and other methods which impose conformational constraint on the peptides or their analogs.

Examples of side chain modifications contemplated by the present invention include modification of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH₄ ; amidation with methylacetimidate; acetylation with acetic anhydride; carbamylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6, trinitrobenzene sulfonic acid (TNBS); alkylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5'-phosphate followed by reduction with NaBH₄.

The guanidino group of arginine residues may be modified by the formation of heterocyclic condensation products with reagents such as 2, 3-butanedione, phenylglyoxal and glyoxal.

The carboxyl group may be modified by carbodiimide activation via o-acylisourea formation followed by subsequent derivatisation, for example, to a corresponding amide.

Sulfhydryl groups may be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation to cysteic acid; formation of mixed disulphides with other thiol compounds; reaction with maleimide; maleic anhydride or other substituted maleimide; formation of mercurial derivatives using 4-chloromercuribenzoate, 4-chloromercuriphenylsulfonic acid, phenylmercury chloride, 2-chloromercuric-4-nitrophenol and other mercurials; carbamylation with cyanate at alkaline pH.

Tryptophan residues may be modified by, for example, oxidation with N-bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphonyl halides. Tryosine residues may be altered by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.

Modification of the imidazole ring of a histidine residue may be accomplished by alkylation with iodoacetic acid derivatives or N-carbethoxylation with diethylpyrocarbonate.

Examples of incorporating unnatural amino acids and derivatives during peptide synthesis include, but are not limited to, use of norleucine, 4-amino butyric acid, 4-amino-3-hydroxy-5-phenylpentanoic acid, 6-aminohexanoic acid-, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienyl alanine and/or D-isomers of amino acids.

Immunogenicity can be significantly improved if the antigens are co-administered with adjuvants, commonly used as an 0.05 to 1.0 percent solution in phosphate-buffered saline. Adjuvants enhance the immunogenicity of an antigen but are not necessarily immunogenic themselves. Adjuvants may act by retaining the antigen locally near the site of administration to produce a depot effect facilitating a slow, sustained release of antigen to cells of the immune system. Adjuvants can also attract cells of the immune system to an antigen depot and stimulate such cells to elicit immune responses.

Immunostimulatory agents or adjuvants have been used for many years to improve the host immune responses to, for example, vaccines. Intrinsic adjuvants, such as lipopolysaccharides, normally are the components of the killed or attenuated bacteria used as vaccines. Extrinsic adjuvants are immunomodulators which are typically non-covalently linked to antigens and are formulated to enhance the host immune responses. Thus, adjuvants have been identified that enhance the immune response to antigens delivered parenterally. Some of these adjuvants are toxic, however, and can cause undesirable side-effects, making them unsuitable for use in humans and many animals. Indeed, only aluminum hydroxide and aluminim phosphate (collectively commonly referred to as alum) are routinely used as adjuvants in human and veterinary vaccines. The efficacy of alum in increasing antibody responses to diptheria and tetanus toxoids is will established and, more recently, a HBsAg vaccine has been adjuvanted with alum. While the usefulness of alum is well established for some applications, it has limitations. For example, alum is ineffective for influenza vaccination and inconsistently elicits a cell mediated immune response. The antibodies elicited by alum-adjuvanted antigens are mainly of the IgG1 isotype in the mouse, which may not be optimal for protection by some vaccinal agents.

A wide range of extrinsic adjuvants can provoke potent immune responses to antigens. These include saponins complexed to membrane protein antigens (immune stimulating complexes), pluronic polymers with mineral oil, killed mycobacteria and mineral oil, Freund's complete adjuvant, bacterial products, such as muramyl dipeptide (MDP) and lipopolysaccharide (LPS), as well as lipid A, and liposomes.

To efficiently induce humoral immune responses (HIR) and cell-mediated immunity (CMI), immunogens are emulsified in adjuvants. Many adjuvants are toxic, inducing granulomas, acute and chronic inflammations (Freund's complete adjuvant, FCA), cytolysis (saponins and pluronic polymers) and pyrogenicity, arthritis and anterior uveitis (LPS and MDP). Although FCA is an excellent adjuvant and widely used in research, it is not licensed for use in human or veterinary vaccines because of its toxicity.

Desirable characteristics of ideal adjiuvants include:

(1) lack of toxicity;

(2) ability to stimulate a long-lasting immune response;

(3) simplicity of manufacture and stability in long-term storage;

(4) ability to elicit both CMI and HIR to antigens administered by various routes, if required;

(5) synergy with other adjuvants;

(6) capability of selectively interacting with populations of antigen presenting cells (APC);

(7) ability to specifically elicit appropriate T_(H) 1 or T_(H) 2 cell-specific immune responses; and

(8) ability to selectively increase appropriate antibody isotype levels (for example, IgA) against antigens.

U.S Pat. No. 4,855,283 granted to Lockhoff et al on Aug. 8, 1989 which is incorporated herein by reference thereto teaches glycolipid analogues including N-glycosylamides, N-glycosylureas and N-glycosylcarbamates, each of which is substituted in the sugar residue by an amino acid, as immuno-modulators or adjuvants. Thus, Lockhoff et al. 1991 reported that N-glycolipid analogs displaying structural similarities to the naturally-occurring glycolipids, such as glycosphingolipids and glycoglycerolipids, are capable of eliciting strong immune responses in both herpes simplex virus vaccine and pseudorabies virus vaccine. Some glycolipids have been synthesized from long chain-alkylamines and fatty acids that are linked directly with the sugars through the anomeric carbon atom, to mimic the functions of the naturally occurring lipid residues.

U.S. Pat. No. 4,258,029 granted to Moloney, assigned to the assignee hereof and incorporated herein by reference thereto, teaches that octadecyl tyrosine hydrochloride (OTH) functions as an adjuvant when complexed with tetanus toxoid and formalin inactivated type I, II and III poliomyelitis virus vaccine. Also, Nixon-George et al. 1990, reported that octadecyl esters of aromatic amino acids complexed with a recombinant hepatitis B surface antigen, enhanced the host immune responses against hepatitis B virus.

Lipidation of synthetic peptides has also been used to increase their immunogenicity. Thus, Wiesmuller 1989, describes a peptide with a sequence homologous to a foot-and-mouth disease viral protein coupled to an adjuvant tripalmityl-s-glyceryl-cysteinylserylserine, being a synthetic analogue of the N-terminal part of the lipoprotein from Gram negative bacteria. Furthermore, Deres et al. 1989, reported in vivo priming of viruslpecific cytotoxic T lymphocytes with synthetic lipopeptide vaccine which comprised of modified synthetic peptides derived from influenza virus nucleoprotein by linkage to a lipopeptide, N-palmityl-s- 2,3-bis(palmitylxy)-(2RS)-propyl- R!-cysteine (TPC).

2. Immunoassays

The transferrin receptor, analogs and fragments thereof and/or peptides of the present invention are useful as immunogens, as antigens in immunoassays including enzyme-linked immunosorbent assays (ELISA), RIAs and other non-enzyme linked antibody binding assays or procedures known in the art for the detection of anti-bacterial, Haemophilus, TfR and/or peptide antibodies. In ELISA assays, the transferrin receptor, analogs, fragments and/or peptides corresponding to portions of TfR protein are immobilized onto a selected surface, for example a surface capable of binding proteins or peptides such as the wells of a polystyrene microtiter plate. After washing to remove incompletely adsorbed transferrin receptor, analogs, fragments and/or peptides, a nonspecific protein such as a solution of bovine serum albumin (BSA) or casein that is known to be antigenically neutral with regard to the test sample may be bound to the selected surface. This allows for blocking of nonspecific adsorption sites on the immobilizing surface and thus reduces the background caused by nonspecific bindings of antisera onto the surface. Preferably, the selected peptides are from the conserved regions of Table 2 or Table 3 to enhance the cross-species detection unless one particular bacterial species is to be detected. In that event, a polypeptide is selected which is unique to the TfR of that particular species. Normally, the peptides are in the range of 12 residues and up and preferably 14 to 30 residues. It is understood however, that a mixture of peptides may be used either as an immunogen in a vaccine or as a diagnostic agent. There may be circumstances where a mixture of peptides from the conserved regions and/or from the non-conserved regions are used to provides cross-species protection and/or diagnosis. In this instance, the mixture of peptide immunogens is commonly referred to as a "cocktail" preparation for use as a vaccine or diagnostic agent.

The immobilizing surface is then contacted with a sample such as clinical or biological materials to be tested in a manner conducive to immune complex (antigen/antibody) formation. This may include diluting the sample with diluents such as BSA, bovine gamma globulin (BGG) and/or phosphate buffered saline (PBS)/Tween. The sample is then allowed to incubate for from 2 to 4 hours, at temperatures such as of the order of 25° to 37° C. Following incubation, the sample-contacted surface is washed to remove non-immunocomplexed material. The washing procedure may include washing with a solution such as PBS/Tween, or a borate buffer.

Following formation of specific immunocomplexes between the test sample and the bound transferrin receptor, analogs, fragments and/or peptides, and subsequent washing, the occurrence, and even amount, of immunocomplex formation may be determined by subjecting the immunocomplex to a second antibody having specificity for the first antibody. If the test sample is of human origin, the second antibody is an antibody having specificity for human immunoglobulins and in general IgG. To provide detecting means, the second antibody may have an associated activity such as an enzymatic activity that will generate, for example, a color development upon incubating with an appropriate chromogenic substrate. Quantification may then achieved by measuring thes degree of color generation using, for example, a visible spectra spectrophotometer.

3. Use of Sequences as Hybridization Probes

The nucleotide sequences of the present invention, comprising the sequence of the transferrin receptor gene, now allow for the identification and cloning of the transferrin receptor genes from any species of Haemophilus and other bacteria that have transferrin receptor genes.

The nucleotide sequences comprising the sequence of the transferrin receptor genes of the present invention are useful for their ability to selectively form duplex molecules with complementary stretches of other TfR genes. Depending on the application, a variety of hybridization conditions may be employed to achieve varying degrees of selectivity of the probe toward the other TfR genes. For a high degree of selectivity, relatively stringent conditions are used to form the duplexes, such as low salt and/or high temperature conditions, such as provided by 0.02M to 0.15M NaCl at temperatures of between about 50° C. to 70° C. For some applications, less stringent hybridization conditions are required such as 0.15M to 0.9M salt, at temperatures ranging from between about 20° C. to 55° C. Hybridization conditions can also be rendered more stringent by the addition of increasing amounts of formamide, to destabilize the hybrid duplex. Thus, particular hybridization conditions can be readily manipulated, and will generally be a method of choice depending on the desired results. In general, convenient hybridization temperatures in the presence of 50% formamide are: 42° C. for a probe which is 95 to 100% homologous to the target fragment, 37° C. for 90 to 95% homology and 32° C. for 85 to 90% homology.

In a clinical diagnostic embodiment, the nucleic acid sequences of the TfR genes of the present invention may be used in combination with an appropriate means, such as a label, for determining hybridization. A wide variety of appropriate indicator means are known in the art, including radioactive, enzymatic or other ligands, such as avidin/biotin, which are capable of providing a detectable signal. In some diagnostic embodiments, an enzyme tag such as urease, alkaline phosphatase or peroxidase, instead of a radioactive tag may be used. In the case of enzyme tags, calorimetric indicator substrates are known which can be employed to provide a means visible to the human eye or spectrophotometrically, to identify specific hybridization with samples containing TfR gene sequences.

The nucleic acid sequences of TfR genes of the present invention are useful as hybridization probes in solution hybridizations and in embodiments employing solid-phase procedures. In embodiments involving solid-phase procedures, the test DNA (or RNA) from samples, such as clinical samples, including exudates, body fluids (e.g., serum, amniotic fluid, middle ear effusion, sputum, bronchoalveolar lavage fluid) or even tissues, is adsorbed or otherwise affixed to a selected matrix or surface. The fixed, single-stranded nucleic acid is then subjected to specific hybridization with selected probes comprising the nucleic acid sequences of the TfR genes or fragments thereof of the present invention under desired conditions. The selected conditions will depend on the particular circumstances based on the particular criteria required depending on, for example, the G+C contents, type of target nucleic acid, source of nucleic acid, size of hybridization probe etc. Following washing of the hybridization surface so as to remove non-specifically bound probe molecules, specific hybridization is detected, or even quantified, by means of the label. As with the selection of peptides, it is preferred to select nucleic acid sequence portions which are conserved among species of Haemophil us, such as nucleic acid sequences encoding the conserved peptide sequence of FIGS. 8, 9, 13 and 14 and particularly listed in Tables 2 and 3. The selected probe may be at least 18 bp and may be in the range of 30 bp to 90 bp long.

4. Expression of the Transferrin Receptor Genes

Plasmid vectors containing replicon and control sequences which are derived from species compatible with the host cell may be used for the expression of the transferrin receptor genes in expression systems. The vector ordinarily carries a replication site, as well as marking sequences which are capable of providing phenotypic selection in transformed cells. For example, E. coli may be transformed using pBR322 which contains genes for ampicillin and tetracycline resistance and thus provides easy means for identifying transformed cells. The pBR322 plasmid, or other microbial plasmid or phage must also contain, or be modified to contain, promoters which can be used by the host cell for expression of its own proteins.

In addition, phage vectors containing replicon and control sequences that are compatible with the host can be used as a transforming vector in connection with these hosts. For example, the phage in lambda GEM™-11 may be utilized in making recombinant phage vectors which can be used to transform host cells, such as E. coli LE392.

Promoters commonly used in recombinant: DNA construction include the β-lactamase (penicillinase) and lactose promoter systems (Chang et al., 1978: Itakura et al., 1977 Goeddel et al., 1979; Goeddel et al., 1980) and other microbial promoters such as the T7 promoter system (U.S. Pat. No. 4,952,496). Details concerning the nucleotide sequences of promoters are known, enabling a skilled worker to ligate them functionally with genes. The particular promoter used will generally be a matter of choice depending upon the desired results. Hosts that are appropriate for expression of the transferrin receptor genes, fragment analogs or variants thereof include E. coli, Bacillus species, Haemophilus, fungi, yeast or the baculovirus expression system may be used.

In accordance with this invention, it is preferred to make the protein by recombinant methods, particularly when the naturally occurring TfR protein as purified from a culture of a species of Haemophilus may include trace amounts of toxic materials or other contaminants. This problem can be avoided by using recombinantly produced TfR protein in heterologous systems which can be isolated from the host in a manner to minimize contaminants in the purified material. Particularly desirable hosts for expression in this regard include Gram positive bacteria which do not have LPS and are therefore endotoxin free. Such hosts include species of Bacillus and may be particularly useful for the production of non-pyrogenic transferrin receptor, fragments or analogs thereof. Furthermore, recombinant methods of production permit the manufacture of Tbp1 or Tbp2 or fragments thereof separate from one another which is distinct from the normal combined proteins present in Haemophilus.

Biological Deposits

Certain plasmids that contain at least a portion coding for a transferrin receptor from strains of Haemophilus influenzae that are described and referred to herein have been deposited with the American Type Culture Collection (ATCC) located at Rockville, Md. USA pursuant to the Budapest Treaty and prior to the filing of this application. Samples of the deposited plasmids will become available to the public upon grant of a patent based upon this United States patent application.

The invention described and claimed herein is not to be limited in scope by plasmids deposited, since the deposited embodiment is intended only as an illustration of the invention. Any equivalent or similar plasmids that encode similar or equivalent antigens as described in this application are within the scope of the invention.

    ______________________________________     Deposit Summary                  ATCC     Clone        Designation                            Date Deposited     ______________________________________     DS-712-1-3   75603     November 4, 1993     JB-1042-7-6  75607     November 4, 1993     JB-1424-2-8  75937     October 27, 1994     JB-1600-1    75935     October 27, 1994     JB-1468-29   75936     October 27, 1994     pT7TBP2A     75931     October 27, 1994     pT7TBP2B     75932     October 27, 1994     pT7TBP2C     75933     October 27, 1994     p17TBP2D     75934     October 27, 1994     ______________________________________

Strains of Haemophilus

Hib strain Eagan is available from Connaught Laboratories Limited, 1755 Steeles Ave. W., Willowdale, Ontario, Canada M2R 3T4.

Hib strain MinnA was obtained from the collection of Dr. Robert Munson, Department of Microbiology and Immunology, Washington University School of Medicine, Children's Hospital, St. Louis, Mo. 63110.

Hib strain DL63 was obtained from the collection of Dr. Eric Hansen, Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Tex. 75235-9048.

PAK 12085 was obtained from the collection of Dr. Robert Munson (supra).

SB12, 29, 30, 32 and 33 were obtained from the collection of Dr. Stephen Barenkamp, Department of Pediatrics, School of Medicine, Saint Louis University Medical Centre, St. Louis, Mo. 63104.

EXAMPLES

The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific Examples. These Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitations.

Methods of molecular genetics, protein biochemistry, immunology and fermentation technology used but not explicitly described in this disclosure and these Examples are amply reported in the scientific literature and are well within the ability of those skilled in the art.

Example 1

This Example illustrates the preparation of chromosomal DNA from H. influenzae strains DL63, Eagan, MinnA, and PAK 12085, and SB33.

H. influenzae strains were grown on Mueller-Hinton agar or in brain heart infusion broth as described by Harkness et al 1992.

A. Chromosomal DNA Extraction from Haemophilus Influenza Type b DL63

Chromosomal DNA was prepared as follows. Two hundred and fifty ml of culture were pelleted by centrifugation at 8,000 rpm in a Beckman J14 rotor for 15 minutes. The pellet was washed with 200 ml of 50 mM Tris-HCl, pH 8.0, centrifuged as before, resuspended in 12.5 ml of 50 mM Tris-HCl, 50 mM EDTA, pH 8.0, and frozen at -20° C. Then 1.25 ml of a 10 mg/ml lysozyme solution in 0.25M Tris-HCl, pH 8.0, was added to the frozen cell pellet. The pellet was thawed and incubated on ice for 45 minutes. Next, 2.5 ml of a solution of 1 mg/ml proteinase K in 0.5% SDS, 0.4M EDTA, 50 mM Tris-HCl, pH 7.5 was added and the mixture incubated at 50° C. for 1 hour with occasional mixing. The lysate was extracted once with 15 ml of Tris-buffered phenol, then 1.5 ml of 3M sodium acetate and 30 ml of ethanol were added to precipitate the DNA. The DNA was spooled on a glass rod, then dissolved in 12.5 ml of 50 mM Tris-HCl, 1 mM EDTA, pH 7.5 containing 0.2 mg/ml RNAse A by rocking overnight. The sample was extracted once with an equal volume of chloroform, precipitated, and spooled as above. The DNA was dissolved in 2 ml of 50 mM Tris-HCl, 1 mM EDTA, pH 7.5 and stored at 4° C.

B. Chromosomal DNA Extraction from Haemophilus Influenzae Type b Eagan

Fifty ml of culture were pelleted by centrifugation, the pellet resuspended in 25 ml of TE (10 mM Tris, 1 mM EDTA, pH 7.5), and 2×5 ml aliquots used for chromosomal DNA preparation. To each aliquot was added 0.6 ml of 10% sarkosyl and 0.15 ml of 20 mg/ml proteinase K and the samples incubated at 37° C. for 1 hour. The lysate was extracted once with Tris-saturated phenol and three times with chloroform:isoamyl alcohol (24:1). The aqueous phases were pooled for a final volume of 7 ml. Then 0.7 ml of 3M sodium acetate (pH 5.2) and 4.3 ml of isopropanol were added to precipitate the DNA which was spooled, rinsed with 70% ethanol, dried, and resuspended in 1 ml of water.

C. Chromosomal DNA Extraction from Haemophilus influenzae Eagan, MinnA, PAK 12085 and SB33

Cells were pelleted from 50 ml of culture by centrifugation at 5000 rpm for 15-20 minutes, at 4° C. The cell pellet was resuspended in 10 ml of TE (10 mM Tris-HCl, 1 mM EDTA, pH 7.5), pronase and SDS were added to final concentrations of 500 μg/ml and 1%, respectively. The sample was incubated at 37° C. for 4 hours until a clear lysate was obtained. The lysate was extracted once with Tris-saturated phenol, once with Tris-saturated phenol/chloroform (1:1), and once with chloroform. The final aqueous phase was dialysec for 24 hours against 2×500 ml of 1M NaCl at 4° C., changing the buffer once, and for 24 hours against 2×500 ml of TE at 4° C., changing the buffer once. The final dialysate was aliquotted for use.

Example 2

This Example illustrates the preparation of chromosomal libraries.

A. H. influenzae DL63-λZAP Library

100 μg of H. influenzae DL63 chromosomal DNA in TE was mechanically sheared in a 1 ml syringe with a 25 gauge needle. The sheared DNA was made blunt-ended by adding water to a final volume of 405 μl, 45 μl of 10×S1 nuclease buffer (2M NaCl, 500 mM NaOAc, pH 4.5, 10 mM ZnSO₄, 5% glycerol), and 1.7 μl of S1 nuclease at 100 U/μl and incubating at 37° C. for 15 min. The sample was extracted once with phenol/chloroform and once with chloroform and 1 ml of ethanol was added to precipitate the DNA. The sample was incubated on ice for 10 min or at -20° C. overnight and the DNA was harvested by centrifugation in a microfuge for 30 minutes. The DNA was washed with 70% ethanol and dried. The Eco RI sites in the DNA sequence were methylated using standard procedures. To this methylated DNA was added 5 μl of 100 mM MgCl₂, 8 μl of dNTP mix (2.5 mM each of dATP, dCTP, dGTP, and dTTP), and 4 μl of 5 U/μl Klenow. The mixture was incubated at 12° C. for 30 minutes. 450 μl of STE (0.1 M NaCl, 10 mM Tris-HCl, 1 mM EDTA, pH 8.0) were added, and the mixture extracted once with phenol/chlofroform, and once with chloroform, before adding 1 ml of ethanol to precipitate the DNA. The sample was incubated on ice for 10 min or at -20° C. overnight. The DNA was harvested by centrifugation in a microfuge for 30 minutes, washed with 70% ethanol and dried.

The DNA was resuspended in 7 μl of TE and to the solution was added 14 μl of phosphorylated Eco RI linkers (200 ng/μl) , 3 μl of 10× ligation buffer, 3 μl of 10 mM ATP, and 3 μl of T4 DNA ligase (4 U/μl). The sample was incubated at 4° C. overnight, then incubated at 68° C. for 10 minutes to inactivate the ligase. To the mixture was added 218 μl of H₂ O, 45 μl of 10× Universal buffer, and 7 μl of Eco RI at 30 U/μl. After incubation at 37° C. for 1.5 hours, 1.5 μl of 0.5M EDTA was added, and the mixture placed on ice.

The DNA was size fractionated on a sucrose gradient, pooling fractions containing DNA of 6-10 kb. The pooled DNA was ethanol precipitated and resuspended in 5 μl of TE buffer. 200 ng of insert DNA was ligated for 2-3 days at 4° C. with 1 μg of ZAP II vector in a final volume of 5 μl. The ligation mixture was packaged using Gigapack II Gold (Stratagene) and plated on E. coli SURE cells on NZY plates. The library was titrated, amplified, and stored at 4° C. under 0.3% chloroform.

B. H. influenzae Eagan-pUC Library

Chromosomal DNA prepared from H. influenzae Eagan by the method in Example 1C was digested with Sau3A I for 2, 5, and 10 minutes and samples electrophoresed on a preparative agarose gel. Gel slices which included DNA fragments between 3-10 kb in length were excised and the DNA extracted by the standard freeze-thaw procedure. Plasmid DNA from pUC 8:2 (pUC 8 with additional Bgl II and Xba I restriction enzyme sites in the multiple cloning site) was digested with BamH I and Bgl II, and dephosphorylated with calf alkaline phosphatase (CAP). The fragments of H. influenzae Eagan DNA were ligated into pUC and the mixture used to transform E. coli JM109 cells.

C. H. influenzae Eagan-λZAP Library

Chromosomal DNA from H. influenzae Eagan prepared as in Example 1B was digested with Eco RI and size fractionated on a preparative agarose gel. Gel slices corresponding to DNA fragments of 7-23 kb were excised and DNA was electroeluted overnight in dialysis tubing containing 3 ml of TAE (40 mM Tris-acetate, 1 mM EDTA) at 14 V. The DNA was precipitated twice and resuspended in water before being ligated overnight with Eco RI digested λZAP II DNA. The ligation mixture was packaged using the Gigapack II packaging kit (Stratagene) and plated on E. coli XL1-Blue cells. The library was titrated, amplified, and stored at 4° C. under 0.3% chloroform.

D. EMBL3 Libraries

H. influenzae MinnA chromosomal DNA (10 μg) was prepared as in Example 1C and digested with Sau3A I (40 units) for 2, 4, and 6 minutes then size-fractionated on a 10-30% sucrose gradient in TNE buffer (20 mM Tris-HCl, 5 mM NaCl, 1 mM EDTA, pH 8). Fractions containing DNA fragments greater than 5 kb were pooled and precipitated. In a second experiment, chromosomal DNA (2.6 μg) was digested with Sau3A I (4 units) for 1, 2, and 3 minutes and size-fractionated by preparative agarose gel electrophoresis. Gel slices containing DNA fragments of 10-20 kb were excised and DNA extracted by a standard freeze/thaw technique. The size-fractionated DNA from the two experiments was pooled for ligation with BamH I arms of EMBL3 (Promega). The ligation mixture was packaged using the Gigapack II packaging kit and plated on E. coli LE392 cells. The library was titrated, then amplified and stored at 4° C. under 0.3% chloroform.

Chromosomal DNA from H. influenzae PAK 12085 or SB33 prepared as in Example 1C was digested with Sau3A I (0.5 units/10 μg DNA) at 37° C. for 15 minutes and size-fractionated by agarose gel electrophoresis. Gel slices corresponding to DNA fragments of 15-23 kb were excised and DNA was electroeluted overnight in dialysis tubing containing 3 ml of TAE at 14 V. The DNA was precipitated twice and resuspended in water before overnight ligation with EMBL3 BamH I arms (Promega). The ligation mixture was packaged using the Lambda in vitro packaging kit (Amersham) according to the manufacturer's instructions and plated onto E. coli NM539 cells. The library was titrated, then amplified, and stored at 4° C. in the presence of 0.3% chloroform.

Example 3

This Example illustrates screening of the libraries

A. H. influenzae DL63-λZAP Expression Library

Tbp1 and Tbp2 proteins were affinity purified on solid phase human transferrin (hTf). Briefly, a 20 ml hTf-Sepharose column was prepared according to the manufacturer's protocol for coupling protein ligands to CNBr-activated Sepharose (Sigma). The resulting matrix was washed with 3 column volumes of 50 mM Tris-HCl, 1M NaCl, 6M guanidine-HCl, pH 8.0 to remove non-covalently bound hTf. The column was then equilibrated with 50 mM Tris-HCl, pH 8.0 and bound hTf was iron loaded using 1 ml of 10 mg/ml FeCl₃ in buffer containing 100 mM each of sodium citrate and sodium bicarbonate, pH 8.6, followed by 2 column volumes of 50 mM Tris-HCl, 1M NaCl, pH 8.0. Total bacterial membranes (300 mg total protein) were prepared from H. influenzae strain DL63 grown on iron deficient media as described previously (Schryvers et al., 1989). Membranes were diluted to 2 mg/ml in 50 mM Tris-HCl, 1M NaCl, pH 8.0 and solubilized by the addition of EDTA to 15 mM and Sarkosyl NL97 to 1.55. After centrifugation at 40,000×g for 1 hour, the supernatant was applied to the hTf column and the column washed with 10 column volumes of 50 mM Tris-HCl, 1M NaCl, 10 mM EDTA, 0.5% Sarkosyl, pH 8.0. The receptor proteins were eluted using 2M GnHCl in the same buffer and the eluted fractions were dialysed extensively against 25 mM ammonium bicarbonate buffer (5 buffer changes), lyophilized, and stored at -20° C. Isolated proteins were used to generate transferrin receptor-specific antisera in New Zealand White rabbits using standard techniques. Briefly, rabbits were immunized 3 times subcutaneously, at intervals of two weeks, using complete Freund's adjuvant for the first injection and incomplete Freund's adjuvant for subsequent injections.

The DL63 λZAP library was plated on E. coli SURE cells and plaques were transferred onto nitrocellulose membranes which had been pre-soaked in 10 mM IPTG to induce expression from the pBluescript lacZ promoter. Filters were blocked using 0.5% skim milk in 50 mM Tris-HCl, 150 mM NaCl, pH 7.5, prior to being probed with the polyclonal anti-TfR antisera and horse radish peroxidase-conjugated goat anti-rabbit IgG. Plaques were purified by 3 rounds of screening and recombinant pBlueascript plasmids (pBHIT1 and pBHIT2; FIGS. 1A and 2) were recovered by the in vivo excision procedure (Short et al., 1988).

B. Eagan, MinnA, and PAK 12085 Non-expression Libraries

(i) Screening of H. influenzae Eagan-pUC library Colony lifts onto nitrocellulose were performed using standard techniques and the filters were probed with the 5'pBHIT2 probe of the transferrin receptor gene illustrated in FIG. 2. The probe was labelled with digoxigenin (dig, Boehringer Mannheim) following the manufacturer's specifications. Several putative clones were dot blotted onto nitrocellulose and submitted to second round screening using the same 5'pBHIT2 probe. Second round putatives were analysed by restriction enzyme mapping and clone S-4368-3-3 (FIG. 1B, FIG. 2) was selected for sequence analysis.

(ii) screening H. influenzae Eagan-λZAP library

The phage library was plated using standard techniques on XLI Blue cells (Stratagene) using LB plates and a 0.7% agarose overlay layer. Plaques were lifted onto nitrocellulose using standard protocols and the filters were baked at 80° C., for 2 hours, under vacuum, to fix the DNA. The 5'pBHIT2 probe of the transferrin receptor gene (FIG. 2) was labelled with digoxigenin and the filters were pre-hybridized for 4 hours at 42° C., then hybridized with the labelled probe at 42° C., overnight. The filters were washed at 68° C. and after autoradiography, several plaques were selected for second round screening. In vivo excision of phagemid DNA from second round putatives was performed according to protocols provided with the λZAP system (Promega). Four clones with identical ˜2.5 kb Eco RI inserts were obtained of which JB-901-5-3 in FIG. B, FIG. 2 is an example. Putative plaques were also amplified and phage DNA was purified from 500 ml of culture. Insert DNA was excised by digestion with Xba I and was cloned into pUC 8:2 (pUC 8 containing additional Bgl II and Xba I sites in its multiple cloning site) which had been digested with Xba I and dephosphorylated. Clone JB-911-3-2 (FIG. 17) contains the 3'-half of the H. influenzae Eagan TfR operon.

(iii) Screening EMBL 3 libraries

The H. influenzae MinnA library was plated onto LE392 cells on NZCYM plates using 0.7% top agarose in NZCYM as overlay. Plaque lifts onto nitrocellulose filters were performed following standard procedures, and filters were processed and probed with the 5'pBHIT2 probe (FIG. 2) labelled with digoxigenin. Putative plaques were plated and submitted to second and third rounds of screening using the same procedures. Phage DNA was prepared from 500 ml of culture using standard techniques, the insert DNA excised by Sal I digestion, and cloned into pUC to generate clone DS-712-1-3 FIGS. 1C and 2).

The H. influenzae PAK 12085 library was plated on LE392 cells on NZCYM plates using 0.7% agarose in NZCYM as overlay. Plaques were lifted onto nitrocellulose and filters were processed and probed with the digoxigenin-labelled 5'pEHIT2 probe (FIG. 2). Putative plaques were plated and subjected to a second round of screening using the same procedures. Phage DNA was prepared from 500 ml cultures-by standard techniques, the DNA insert was excised by digestion with Sal I, and cloned into pUC to generate clone JB-1042-7-6 (FIGS. 1D and 2).

The H. influenzae SB33 library was plated on LE392 cells on NZCYM plates using 0.7% agarose in NZCYM as overlay. Plaques were lifted onto nitrocellulose and filters were processed and probed with the digoxigenin-labelled 5'pBHIT2 probe (FIG. 2). Putative plaques were plated and subjected to a second round of screening using the same procedures. Phage DNA was prepared from 500 ml cultures by standard techniques, the DNA insert was excised by digestion with Sal I, and cloned into pUC to generate clone JB-1031-2-9 (FIG. 2).

Example 4

This Example illustrates the sequencing of the Tbp1 and Tbp2 genes of the TfR operon.

Plasmid DNA from clones pBHIT 1, pBHIT 2, S-4368-3-3, JB-901-5-3, DS-712-1-3, JB-1042-7-6 and JB-1031-2-9 was prepared using standard techniques. Oligonucleotide sequencing primers of 17-25 bases in length were synthesized on the ABI model 380B DNA Synthesizer and purified by chromatography using OPC cartridges obtained from Applied Biosystems Inc., and used in accordance with the manufactures recommendations. Samples were sequenced using the ABI model 370A DNA Sequencer and dye terminator chemistry according to manufacturers' protocols. The sequence of the TfR operon from strain DL63 is illustrated in FIG. 3, that of strain Eagan in FIG. 4, that of strain MinnA in FIG. 5, that of PAK 12085 in FIG. 6 and that of SB33 in FIG. 7.

Example 5

This Example illustrates the PCR amplification of the tbp2 genes from non-typable H. influenzae strains SB12, SB29, SB30, and SB32.

Chromosomal DNA from non-typable H. influenzae strains SB12, SB29, SB30, and SB32 was prepared as described above. The TfR genes are arranged as an operon with tbp2 followed by tbp1 (see FIGS. 12A and 12B). Oligonucleotides were synthesized to the 5'-end of the tbp2 and the reverse complement of the 5'-end of the tbp1 coding sequences. The primers were: GGATCCATATGAAATCTGT ACCTCTTATCTCTGGT (SEQ ID NO: 120) corresponding to MKSVPLISGS (SEQ ID NO: 147) from the leader sequence of Tbp2 and TCTAGAAGCTTTTTTAGTCATTTTTAGTATTCCAT (SEQ ID NO: 137) which is the reverse complement of the leader sequence MTKK (SEQ ID NO: 138) of Tbp1 and a part of the intergenic sequence (FIGS. 12A and 12B). PCR amplification was performed in buffer containing 10 mM Tris/HCl pH 8.3, 50 mM potassium chloride and 1.5 mM magnesium chloride. Each 100 μl reaction mixture contained 5 ng of chromosomal DNA, 1 μg of each primer, 5 units amplitaq DNA polymerase (Perkin Elmer Cetus) and 0.4 mM dNTPs (Perkin Elmer Cetus). The cycling conditions were 25 cycles of 94° C. for 1.0 min, 45° C. for 2.0 min and 72° C. for 1.5 min. Specific 2 kb fragments were amplified for each sample (FIG. 13). SB33 DNA was used as a positive control (Lane 1). Chromosomal DNA used for amplification of the Tbp2 gene were lane 1, SB33; lane 2, SB12; lane 3, SB29; lane 4, SB30; and lane 5, SB32. The fragments were cloned into the TA cloning vector (Invitrogen) and their nucleotide sequences determined. The nucleic acid sequences of Tbp2 from strains SB12 (SEQ ID NO: 108), SB29 (SEQ ID NO: 110), SB30 (SEQ ID NO: 112) and SB32 (SEQ ID NO: 114) are shown in FIGS. 8, 9 10 and 11 respectively.

Example 6

This Example illustrates the comparison of the amino acid sequences of transferrin the identification of potentially exposed epitopes of transferrin receptor proteins by secondary structure analysis.

Referring to FIG. 14, there is shown a comparison of the amino acid sequence of Tbp1 from H. influenzae type b Eagan, DL63, non-typable H. influenzae strains PAK 12085 and SB33, N. meningitidis strains B16B6 and M982 (Legrain et al., 1993) and N. gonorrhoeae FA19 (Cornelissen et al., 1992). This analysis revealed regions of Tbp1 which are conserved among all these bacteria.

Referring to FIG. 15, there is shown a comparison of the amino acid sequence of Tbp2 from H. influenzae type b strains Eagan, DL63, non-typable H. influenzae PAK 12085, SB12, SB29, SB30 and SB32, N. meningitidis strains B16B6 and M982, N. gonorrhoeae FA19 and Actinobacillus (Haemophilus) pleuropneumoniae (Gerlach et al., 1992) 205 and 37. This analysis revealed regions of Tbp2 which are conserved among all these bacteria.

Protein secondary structure analyses were performed using the Chou and Fasman algorithms (1978) and hydrophilicity/hydrophobicity plots were performed using the Hopp algorithm (1986). The values were derived from the averages of heptapeptide windows and are plotted at the midpoint of each fragment. FIG. 16A illustrates the predicted secondary structure of Tbp1 from H. influenzae type b Eagan and FIG. 16B illustrates the predicted secondary structure of Tbp2 from H. influenzae type b Eagan. The predicted secondary structures depicted in FIGS. 16A and 16B were arrived at using the procedures described above. However, the inventors have not yet been able to verify that the secondary structure is accurately depicted by these Figures.

Conserved epitopes of Tbp1 and Tbp2 proteins from several different bacteria were identified by sequence alignment as shown in FIGS. 14 and 15 respectively. Some such conserved epitopes include:

    ______________________________________     TBP1     DNEVTGLGK          SEQ ID NO:43     TBP1     EQVLNIRLTRYDPGI    SEQ ID NO:44     TBP1     GAINEIEYENVKAVEISKG                                 SEQ ID NO:45     TBP1     GALAGSV            SEQ ID NO:46     TBP2     LEGGFYGP           SEQ ID NO:74     TBP2     CSGGGSFD           SEQ ID NO:75     TBP2     YVYSGL             SEQ ID NO:76     TBP2     CCSNLSYVKFG        SEQ ID NO:77     TBP2     FLLGHRT            SEQ ID NO:78     TBP2     EFNVDF             SEQ ID NO:79     TBP2     NAFTGTA            SEQ ID NO:80     TBP2     VNGAFYG            SEQ ID NO:81     TBP2     LEGGYF             SEQ ID NO:82     TBP2     VVFGAR             SEQ ID NO:83     ______________________________________

Furthermore, in combination with the predicted secondary structures, four conserved exposed epitopes were identified on Tbp1 and two were identified on Tbp2. These are:

    ______________________________________     Tbp1  DNEVTGLGK       SEQ ID NO: 43     Tbp1  EQVLN/DIRDLTRYD SEQ ID NOS: 139 and 140     Tbp1  GAINEIEYENVKAVEISK                           SEQ ID NO: 141     Tbp1  GI/VYNLF/LNYRYVTWE                           SEQ ID NOS: 142 and 143     Tbp2  CS/LGGG(G)SFD   SEQ ID NOS: 75, 144 and 145     Tbp2  LE/SGGFY/FGP    SEQ ID NOS: 74 and 146     ______________________________________

Proteins, polypeptides or peptides containing the afore-mentioned conserved amino acid sequences are particularly useful as detecting means in diagnostic embodiments and as immunogens to detect or protect from diseases caused by bacteria that produce transferrin receptor protein. For immunization, the particularly indicated amino acid sequences may be presented to the immune system as proteins or peptides or a live delivery vehicle, such as Salmonella, BCG, adenovirus, poxvirus, vaccinia or poliovirus may be used.

Example 7

This Example illustrates the construction of plasmid JB-1468-29 which expresses Eagan Tbp1 from E.coli.

Plasmids S-4368-3-3 (FIGS. 1B and 2) and JB-911-3-2 (FIG. 17) contain the 5'- and 3'- parts of the Eagan tbp1 gene, respectively. FIG. 17 illustrates the construction scheme for plasmid JB-1468-29. The oligonucleotide sequences used in the construction of JB-1468-29 are shown in FIG. 20, (SEQ ID NOS: 86 and 87). Plasmid JB-1468-29 was introduced into E. coli strain BL21/DE3 by electroporation to generate strain JB-1476-21.

JB-1476-2-1 was grown in YT medium and induced with IPTG following standard protocols. For preparation of Tbp1 for immunogenicity and other studies, strain JB-1476-2-1 was grown overnight in NZCYM media containing 3% glucose. A 1:40 inoculum was added to fresh NZCYM media without glucose, and the culture grown to A₅₇₈ =0.3. Lactose was added to 1% and the culture was induced for 4 hours. SDS-PAGE analysis of whole cell lysates of JB-1476-2-1 is shown in FIG. 22. Lane 1, JB-1476-2-1 (T7/Eagan Tbp1) at t_(o) ; lane 2, JB-1476-2-1 at t=4h induction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) at t_(o) ; lane 5, JB-1437-4-1 at t=4h induction; lane 6, JB-1607-1-1 (T7/SB12 Tbp2) at t_(o) ; lane 7, JB-1607-1-1 at t=4h induction.

Example 8

This Example illustrates the construction or plasmid JB-1424-2-8 which expresses Eagan Tbp2 from E. coli.

Referring to FIG. 18, there is shown plasmid S-4368-3-3 which contains the entire tbp2 gene from H. influenzae type b Eagan. FIG. 18 illustrates plasmid JB-1424-2-8 and FIG. 19 shows the oligonucleotides used. Plasmid JB-1424-2-8 was introduced into E. coli strain BL21/DE3 by electroporation to generate E. coli strain JB-1437-4-1. Upon induction with IPTG or lactose, Tbp2 was expressed by E. coli JB-1437-4-1 as shown in FIG. 22. Lane 1, JB-1476-2-1 (T7/Eagan Tbp1) at t_(o) ; lane 2, JB-1476-2-1 at t=4h induction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) at t_(o) ; lane 5, JB-1437-4-1 at t=4h induction; lane 6, JB-1607-1-1 (T7/SB12 Tbp2) at t_(o) ; lane 7, JB-1607-1-1 at t=4h induction.

Example 9

This Example illustrates the construction of plasmids which encode a lipoprotein leader sequence before the Tbp2 sequence.

Oligonucleotides used for the construction of plasmids with lipoprotein leader sequences derived from E. coli lpp (SEQ ID NOS: 88 and 89), rlpB (SEQ ID NOS: 90 and 91), and pal (SEQ ID NOS: 92 and 93) preceeding Tbp2 are shown in FIG. 20. Plasmids constructed and corresponding strains generated are illustrated in Table 1 below.

Example 10

This Example illustrates the construction of plasmid JB-1600-1 which expresses SB12 Tbp2 from E. coli. Plasmid DS-1047-1-2 (FIG. 21) contains the PCR-amplified SB12 tbp2 gene. The tbp2 gene was excised as a Nde I to EcoR I restriction fragment and inserted into the pT7-7 expression vector to generate plasmid JB-1600-1. Electroporation into BL21/DE3 cells yielded E. coli strain JB-1607-1-1 which expresses SB12 Tbp2. Upon induction with IPTG or lactose, SB12 Tbp2 was expressed, as shown in FIG. 22. Lane 1, JB-1476-2-1 (T7/Eagan Tbp1) at t_(o) ; lane 2, JB-1476-2-1 at t=4h induction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) at t_(o) ; lane 5, JB-1437-4-1 at t=4h induction; lane 6, JB-1607-1-1 (T7/SB12 Tbp2) at t_(o) ; lane 7, JB-1607-1-1 at t=4h induction.

Example 11

This Example illustrates the extraction and purification of Tbp1 and Tbp2.

The purification scheme for Tbp1 and Tbp2 is shown in FIG. 23. Both recombinant proteins are expressed as inclusion bodies in E. coli and the purification schemes are identical. Cells from a 500 ml culture, prepared as described in Example 7 for Tbp1 and in Example 8 for Tbp2, were resuspended in 50 ml of 50 mM Tris-HCl, pH 8.0, and disrupted by sonication (3×10 min, 70% duty circle). The extract was centrifuged at 20,000×g for 30 min and the resultant supernatant which contained>95% of the soluble E. coli proteins was discarded.

The remaining pellet (FIG. 23, PPT₁) was further extracted in 50 ml of 50 mM Tris, pH 8.0 containing 0.5% Triton X-100 and 10 mM EDTA. After centrifugation at 20,000×g for 30 min, the supernatant containing residual soluble proteins and the majority of the membrane proteins, was discarded. The resultant pellet (FIG. 23, PPT₂) obtained after the above extraction, contained the inclusion bodies. The Tbp1 and Tbp2 proteins were solubilized in 50 mM Tris, pH 8.0, containing 0.1% SDS and 5 mM DTT. After centrifugation, the resultant supernatant was further purified on a Superdex 200 gel filtration column equilibrated in 50 mM Tris, pH 8.0, containing 0.1% SDS and 5 mM DTT. The fractions were analysed by SDS PAGE and those containing purified Tbp1 or Tbp2 were dialysed overnight at 4° C. against 50 mM Tris, pH 8.0 and then centrifuged at 20,000×g for 30 min. The protein remained soluble under these conditions and the purified Tbp1 and Tbp2 were stored at -20° C.

The SDS-PAGE analysis of the purification process is shown in FIG. 24. Lanes 1, prestained molecular weight protein markers (106, 80, 49.5, 32.5, 27.5, 18.5 kDa); lanes 2, E.coli whole cell lysates; lanes 3, solubilized inclusion bodies; lanes 4, purified Tbp1 or Tbp2.

Example 12

This Example illustrates immunogenicity studies of recombinant Tbp1 and Tbp2 in mice.

Groups of five Balb/c mice were injected subcutaneously (s.c.) on days 1, 29 and 43 with purified rTbp1 or rTbp2 (1 μg to 10 μg), prepared as described in Example 11, in the presence of A1PO₄ (1.5 mg per dose). Blood samples were taken on days 14, 28, 42 and 56 for analysis of the anti-rTbp1 and anti-rTbp2 antibody titers by EIA. The results of the immunogenicity studies are illustrated in FIG. 25.

Example 13

This Example illustrates the development of EIAs for determination of anti-rTbp1 and anti-rTbp2 antibodies in mouse sera.

Anti-rTbp1 and anti-rTbp2 antibody titres were determined essentially as described by Panezutti et al. (1993). Microtiter wells were coated with 0.5 μg of rTbp1 or rTbp2, prepared as described in Example 11, for 16 h at room temperature, then blocked with 0.1% (w/v) BSA in PBS. The sera were serially diluted, added to the wells, then incubated for one hour at room temperature. Affinity-purified F(ab')₂ fragments of goat anti-mouse IgG (Fc specific) antibody conjugated to horseradish peroxidase were used as second antibody. The reactions were developed using tetramethylbenzidine (TMB/H₂ O₂) and the absorbance was measured at 450 nm (using 540 nm as a reference wavelength) in a Flow Multiskan MCC microplate reader. The reactive titer of an antiserum was defined as the reciprocal of the dilution consistently showing a two-fold increase in absorbance over that obtained with the pre-immune serum sample.

Example 14

This Example illustrates the cross-reactivity of anti-Tbp1 antisera, produced by immunization with recombinant Eagan Tbp1, with various strains of H. influenzae.

Whole cell lysates of H. influenzae strains grown in BHI media supplemented with NAD and heme (Harkness et al., 1992) ±EDDA were separated by SDS PAGE gel, transferred to nitrocellulose membrane, and probed with guinea pig anti-Tbp1 antisera raised to purified recombinant Eagan Tbp1 (FIG. 26). Lane 1, BL21/DE3; lane 2, SB12-EDDA; lane 3, SB12 +EDDA; lane 4, SB29-EDDA; lane 5, SB29 +EDDA; lane 6, SB33 -EDDA; lane 7, SB33 +EDDA; lane 8, Eagan -EDDA; lane 9, Eagan +EDDA; lane 10, B. catarrhalis 4223 -EDDA; lane 11, B. catarrhalis 4223 +EDDA; lane 12, N. meningitidis 608 EDDA; lane 13, N. meningitidis 608 +EDDA; lane 14, induced JB-1476-2-1 expressing recombinant Eagan Tbp1; lane 5, molecular weight markers. Specific˜95 kDa bands reacted with the anti-Tbp1 antisera in lanes 3, 4, 5, 7, 8 and 9, corresponding H. influenzae strains SB12, SB29, SB33 and Eagan; ˜110 kDa bands in lanes 10 and 11, corresponding B. catarrhalis strain 4223; and ˜80 kDa bands in lanes 12 and 13, corresponding to N. meningitidis 608.

Example 15

This Example illustrates the cross-reactivity of anti-Tbp2 antisera, produced by immunization with recombinant Eagan Tbp2, with various strains of H. influenzae.

Whole cell lysates of H. influenzae strains grown in BHI media supplemented with NAD and heme (Harkness et al., 1992) ±EDDA were separated on an SDS PAGE gel, transferred to nitrocellulose membrane, and probed with guinea pig anti-Tbp2 antisera raised to purified recombinant Eagan Tbp2 (FIG. 27). Lane 1, molecular weight markers; lane 2, induced JB-1437-4-1 expressing recombinant Eagan Tbp2; lane 3, SB12-EDDA; lane 4, SB12 +EDDA; lane 5, SB29 -EDDA; lane 6, SB29 +EDDA; lane 7, SB30 -EDDA; lane 8, SB30 +EDDA; lane 9, SB32 -EDDA; lane 10, SB33-EDDA; lane 11, SB33 +EDDA; lane 12, PAK -EDDA; lane 13, PAK +EDDA; lane 14, Eagan -EDDA; lane 15, Eagan +EDDA. Specific bands of about 60-70 kDa were reactive with the anti-Tbp2 antisera in lanes 3, 6, 7, 8, 13, 14 and 15, corresponding to Haemophilus strains SB12, SB29, SB30, PAK and Eagan.

Example 16

This Example illustrates the synthesis of synthetic peptides corresponding to conserved regions in Tbp2 and Tbp1.

The deduced amino acid sequences of Tbp1 and Tbp2 were compared as shown in FIGS. 14 and 15 respectively. This comparison identified regions of amino acid sequence conservation within the transferrin receptor described above and, as shown in Tables 2 and 3, peptides were synthesized containing a portion of the transferrin receptor. Such synthesis may be effected by expression in a suitable host of recombinant vectors containing nucleic acid encoding said peptides or by standard peptide synthesis.

Briefly, peptides were synthesized using an ABI 430A peptide synthesizer and optimized t-Boc chemistry using the conditions recommended by the manufacturer, and peptides were cleaved from the resin using hydrofluoric acid (HF). The peptides were purified by reverse-phase high performance liquid chromatography (RP-HPLC) on a Vydac C4 semi-preparative column (1×30 cm) using a 15 to 55% acetonitrile gradient in 0.1% trifluoryl acetic acid (TFA) developed over 40 minutes at a flow rate of 2 ml/minute. All synthetic peptides used in biochemical and immunological studies were >95% pure as judged by analytical HPLC. Amino acid composition analyses were performed on a Waters Pico-Tag system and were in good agreement with the theoretical compositions.

Example 17

This Example illustrates the immunogenicity of synthetic peptides in test animals.

Guinea pigs were immunized intramuscularly with 100 μg of peptide, prepared as described in Example 16, emulsified in Freund's complete adjuvant on day 0 followed by boosters on days +14 and +28 using the same amount of peptide emulsified in Freund's incomplete adjuvant. Sera samples were obtained on day 42+ and antibody titres determined by enzyme-linked immunosorbent assay (ELISA). Briefly, microtiter wells (Nunc-Immunoplate, Nunc, Denmark) were coated with 500 ng of any one particular peptide in 50 μL of coating buffer (15 mM Na₂ CO₃, 35 mM NaHCO₃, pH 9.6) for 16 hours at room temperature. The plates were then blocked with 0.1% (w/v) BSA in phosphate buffer saline (PBS) for 30 minutes at room temperature. The antisera were serially diluted, added to the wells and incubated for 1 hour at room temperature. After removal of the antisera, the plates were washed five times with PBS containing 0.1% (w/v) Tween-20 and 0.1% (w/v) BSA. F(ab')₂ from goat anti-guinea pig IgG antibodies conjugated to horseradish peroxidase (Jackson ImmunoResearch Labs Inc., Pa.) were diluted (1/8,000) with washing buffer, and added onto the microtiter plates. After 1 hour of incubation at room temperature, the plates were washed five times with the washing buffer. The plates were developed using the substrate tetramethylbenzidine (TMB) in H₂ O₂ (ADI, Toronto), the reaction was stopped with 1N H₂ SO₄ and the optical density was measured at 450 nm using a Titretek Multiskan II (Flow Labs., Virginia). Two irrelevant peptides of 32 amino acid residues were included as negative controls in these ELISAs. Assays were performed in triplicate, and the reactive titer of each antiserum was defined as the dilution consistently showing a 2-fold increase in absorbance value over those obtained from the negative controls. The antisera raised in guinea pigs were monospecific for the peptide used for immunization. The titres of the sera obtained following immunization are shown in Table 4.

Peptides of the present invention comprise single copies of any of those shown in Tables 2 and 3 or peptides containing multiple copies of analogs thereof. A peptide may further comprise multiples of different peptides selected from those shown in Tables 2 and 3 or analogs thereof and include suitable carrier molecules. It is preferred that the peptides from (conserved regions be used to develop antibodies because an immuno- or other type of binding assay can then be used to detect several species of Haemophilus. Tables 2 and 3 therefore set out several other conserved regions of transferrin receptor to identify other peptides which would be useful in diagnosis, immunization and medical treatment.

Example 18

This Example describes the ability of antiserum raised against peptides corresponding to conserved portions of transferrin receptor to recognize the transferrin receptor of Branhamella catarrhalis.

Guinea pigs were immunized with peptide, corresponding to conserved portions of transferrin receptor, and antisera obtained are described in Example 17. A whole-cell extract of Branhamella catarrhalis was immunoblotted with the peptide-specific antiserum which specifically recognized the transferrin receptor from this bacterium. Anti-peptide antiserum from a guinea pig immunized with the Tbp2 N-terminal peptide and peptide TBP2-25 specifically recognized Tbp2 protein from Branhamella catarrhalis and recombinant Tbp2 expressed by plasmid clone pBHIT2 in E. coli. Clone pBHIT2 expresses a truncated version of Tbp2 starting at amino acid 80. (i.e. NKKFYSG SEQ ID NO: 105). Therefore, the Tbp2 protein from pBHIT2 can only be recognized by antibodies raised against the second epitope LEGGFYGP (TEP2-25). This analysis shows that peptides corresponding to conserved sequences between transferrin receptor are useful in detecting most, if not all, bacteria that produce transferrin receptor and as components in immunogenic compositions, including vaccines to produce an immune response against transferrin receptor and protect against diseases caused by such bacteria.

The sera from these rabbits were tested by ELISA against a peptide incorporating the sequence LEGGFYGP (SEQ ID NO:74) or against H. influenzae strain DL63, Tbp2. ELISA plates were coated with the peptide or the protein then blocked with 5% skim milk. Serial two-fold dilutions of sera in phosphate buffered saline, 0.05% tween-20, and 1% dried milk were incubated on the plates for two hours at 37° C., following which the plates were washed five times in phosphate buffered saline with 0.05% tween-20. Washed plates were probed with a horse-radish peroxidase (HRPO)-conjugated donkey anti-rabbit IgG for 30 minutes at room temperature, then washed five times in phosphate buffered saline with 0.05% tween-20. HRPO-substrate was added to all wells for 30 minutes at room temperature in the dark, then color developemnt was halted by the addition of 50 ul 1M sulphuric acid. Color was measured by determining absorbance at 450 nm.

Example 19

This Example illustrates the generation of H. influenzae strains that do not produce transferrin receptor.

A 2.55 Eco RI fragment of the insert from pBHIT1 was subcloned into the Eco RI site of pUC4K, resulting in removal of the Tn903 kanamycin resistance (kan) cassette from this vector (pUHIT1; FIG. 28). This subcloning step facilitated the subsequent insertion of either a HincII or PstI pUC4K fragment containing the kan cassette into the Hind III or Pst I sites of pUHIT1 as both are unique sites in this construction to produce pUHIT1KFH and pUHIT1KFP, FIG. 28. Following digestion with Eco RI to remove the interrupted gene sequences, the constructs were introduced into the H. influenzae wild type genome by transformation using M-IV media as described previously (Barcak et al., 1991) and transformants were selected on BHINH agar containing 20 μg/ml kanamycin.

Example 20

This Example illustrates the construction of polioviruses expressing an epitope of a transferrin receptor.

A cDNA clone of bases 1175 to 2956 of the poliovirus type 1, Mahoney strain (PV1-M) genome was cut with restriction enzymes Sau I and Hind III. These enzymes excise a fragment containing bases 2754 to 2786, which encodes PV1-M amino acids 1094 to 1102, as shown in FIG. 29. In this application, we use the four-digit code for poliovirus amino-acids; for example, 1095 is amino acid 95 of capsid protein VP1. New hybrid cDNA clones encoding both poliovirus and transferrin receptor amino-acid sequences were constructed by replacing the excised fragment with synthetic oligonucleotides coding for amino acids from H. influenzae Tbp2. The new hybrid cDNA clones were cut with restriction enzymes Nhe I and SnaB I, which excise a hybrid fragment, including the transferrin receptor DNA sequences, from poliovirus base 2471 to 2956. A cDNA clone, for example pT7XLD or pT7CMCB, of the entire genome of PV1-M was cut with Nhe I and SnaBI to excise a fragment from poliovirus base 2471 to 2956. This was then replaced with a hybrid fragment including the transferrin receptor DNA sequences to produce a hybrid cDNA clone of the genome of PV1-M with bases 2754 to 2786 replaced by bases encoding a hybrid BC loop including transferrin receptor amino acids, as shown in FIG. 29.

The plasmid pT7XLD and clones derived from pT7XLD, such as pT7CMCB, contain a promoter sequence for the enzyme T7 RNA polymerase at the 5' end of the PV1-M CDNA. RNA transcripts of the PV1-M cDNA, including any bases encoding transferrin receptor amino acids, were prepared using T7 RNA polymerase as described by van der Werf et al. Transfection of Vero cells with these RNA transcripts produced four viable hybrid viruses, designated PV1TBP2A, PV1TBP2B, PV1TBP2C and PV1TBP2D. Transfection with transcripts of pT7CMCB yielded a transfection-derived wild-type poliovirus designated PV1XLD (FIG. 29).

The antigenic characteristics of PV1TBP2A, PV1TBP2B, PV1TBP2C and PV1TBP2D are shown in Table 5. All were neutralized by guinea-pig antisera raised against a peptide incorporating the sequence LEGGFYGP (SEQ ID NO: 74), indicating that the viruses expressed this sequence in an antigenically recognisable form. To produce the antisera female guinea pigs were immunized IM with a 500 ul volume containing 200 ug peptide formulated in aluminum phosphate (3 mg/ml). Animals were immunized on days 1, 14, 28 and 42 and bled on days 0, 28, 42 and 56. Sera were from the day 56 bleed. PV1TBP2A and PV1TBP2B were also neutralized by rabbit antisera raised against H. influenzae strain DL63 Tbp2, indicating that at least these two viruses expressed the sequence in a form recognisable to antibodies raised against the protein. All viruses were neutralisable by anti-PV1 sera, indicating that the changes in polio neutralization antigenic site I had not significantly affected other antigenic sites on the viruses.

Example 21

This Example illustrates the use of poliovirus hybrids to induce high titer antisera against Tbp2.

Rabbits were inoculated with CsCl-purified PV1TBP2A (rabbits #40, 41, 42). Note that, although the viruses used were live, poliovirus does not replicate in rabbits and that any response observed is effectively the response to an inactivated antigen. On day 1, rabbits were inoculated with 1 ug of virus in Freund's complete adjuvant subcutaneously on the back, and, on day 14, the rabbits were boosted with 1 ug of virus in Freund's incomplete adjuvant inoculated subcutaneously on the back. The rabbits were bled on day 0 (prebleed) and on day 27. The dose of virus per inoculation was 2.5×10⁸ pfu, which was determined from A₂₆₀ values to be approximately 3.0×10¹¹ virions. This equivalent to 0.5 pmol of virus or 30 pmol of the LEGGFYG (SEQ ID NO: 74) epitope, since each virion expresses 60 copies of the epitope.

SUMMARY OF THE DISCLOSURE

In summary of this disclosure, the present invention provides purified and isolated DNA molecules containing transferrin receptor genes, the sequences of these transferrin receptor genes and the derived amino acid sequences thereof. The invention also provides peptides corresponding to portions of the transferrin receptor. The genes, DNA sequences, recombinant proteins and peptides are useful for diagnosis, immunization and the generation of diagnostic and immunological reagents. Vaccines based upon expressed recombinant Tbp1 and/or Tbp2, portions thereof, or peptides derived from the provided sequences can be prepared for prevention of diseases caused by bacterial pathogens that produce transferrin receptor. Modifications are possible within the scope of this invention.

                  TABLE 1     ______________________________________     leader    1st residue                          plasmid    strain     ______________________________________     E. coli lpp               Cys        JB-1360-1R-10                                     JB-1407-1-1     E. coli lpp               Ser        JB-1366-1R-7                                     JB-1407-3-1     E. coli pal               Cys        JB-1360-3-10                                     JB-1407-2-1     E. coli pal               Ser        JB-1366-3R-5                                     JB-1407-4-4     E. coli rlpB               Cys        JB-1399-1  JB-1437-1-1     E. coli rlpB               Ser        JB-1378-7  JB-1407-5-1     ______________________________________

                                      TABLE 2     __________________________________________________________________________     PREDICTED ANTIGENIC Tbp1 PEPTIDES     PEPTIDE          RESIDUES.sup.1                SEQUENCES                 SEQ ID NO:     __________________________________________________________________________     TBP1-N           1-36 AETQSIKDTKEAISSEVDTQSTEDSELETISVTAEK                                          13     TBP1-2          31-66 SVTAEKVRDRKDNEVTGLGKIIKTSESISREQVLNI                                          14     TBP1-3          59-94 SREQVLNIRDLTRYDPGISVVEQGRGASSGYSIRGM                                          15     TBP1-4           88-123                GYSIRGMDRNRVALLVDGLPQTQSYVVQSPLVARSG                                          16     TBP1-5          117-152                PLVARSGYGTGAINEIEYENVKAVEISKGGSSSEYG                                          17     TBP1-6          147-182                SSSEYGNGALAGSVTFQSKSAADILEGDKSWGIQTK                                          18     TBP1-7          179-214                GIQTKNAYSSKNKGFTHSLAVAGKQGGFEGVAIYTH                                          19     TBP1-8          208-243                GVAIYTHRNSIETQVHKDALKGVQSYDRFIATTEDQ                                          20     TBP1-9          236-271                IATTEDQSAYFVMQDECLDGYDKCKTSPKRPATLST                                          21     TBP1-10          266-301                PAThSTQRETVSVSDYTGANRIKPNPMKYESQSWFL                                          22     TBP1-11          293-328                YESQSWFLRGGYHFSEQHYIGGIFEFTQQKFDIRDM                                          23     TBP1-12          322-357                KPDIRDMTFPAYLRPTEDKDLQSRPFYPKQDYGAYQ                                          24     TBP1-13          352-387                DYGAYQHIGDGRGVKYASGLYFDEHHRKQRVGIEYI                                          25     TBP1-14          383-418                GIEYIYENKKAGIIDKAVLSANQQNIILDSYMRHT                                          26     TBP1-15          412-447                DSYMRHTHCSLYPNPSKNCRPTLDKPYSYYHSDRNV                                          27     TBP1-16          443-478                SDRKVKKEKMMMLQLNLEKKIQQNWLTHQIAFNLGF                                          28     TBP1-17          469-504                THQIAFNLGFDDFTSALQHKDYLTRRVIATASSISE                                          29     TBP1-M          498-534                TASSISEKRGEARRNGLQSSPYLYPTPKAELVGGDLC                                          30     TBP1-19          528-563                LVGGDLCNYQGKSSNYSDCKVRLIKGKNYYFAARNN                                          31     TBP1-20          558-593                FAARNNMALGKYVDLGLGMRYDVSRTKANESTISVG                                          32     TBP1-21          588-623                STISVGKFKNFSWNTGIVIKPTEWLDLSYRLSTGFR                                          33     TBP1-22          618-653                LSTGFRNPSFAEMYGWRYGGKDTDVYIGKFKPETSR                                          34     TBP1-23          648-683                KPETSRNQEFGLALKGDFGNIEISHFSNAYNNLIAF                                          35     TBP1-24          677-712                YNNLIAFAEELSKNGTTGKGNYGYHNAQNAKLVGVN                                          36     TBP1-25          706-741                AKLVGVNITAQLDFNGLWKRIPYGWYATFAYNRVKV                                          37     TBP1-26          735-770                AYNRVKVKDQKINAGLASVSSYLFDAIQPSRYIIGL                                          38     TBP1-27          764-799                SRYIIGLDYDHPSNTWGIKTMFTQSKKKSQNELLGK                                          39     TBP1-28          794-829                NELLGKRALGNNSRKVKSTRKLTRAWHILDVSGYYM                                          40     TBP1-29          825-854                SGYYMVNRSILFRLGVYNLLNYVTWHAV                                          41     TBP1-30          843-865                LLNYRYVTWHAVRQTAQGAEFDI   42     TBP1-31          42-50 DNEVTGLGK                 43     TBP1-32          61-76 EQVLNIRDLTRYDPGI          44     TBP1-33          61-95 EQVLNIRDLTRYDPGISWEQGRGASSGYSIRGMD                                          45     TBP1-34          128-146                GAINEIEYENVKAVEISKG       46     TBP1-35          155-161                GALAGSV                   47     TBP1-1           1-14 AETQSIKDTKEAISC.sup.2     48     __________________________________________________________________________      .sup.1 Residue number from the sequence of Tbp1 of H. influenzae type b      strain Eagan (as shown in FIG. 8).      .sup.2 Cysteine added to facilitate coupling to a carrier protein, for      example KLH.

                                      TABLE 3     __________________________________________________________________________     PREDICTED CONSERVED ANTIGENIC Tbp2 PEPTIDES     PEPTIDE          RESIDUES.sup.1                SEQUENCES                 SEQ ID NO:     __________________________________________________________________________     TBP2-1          18-31 CSGGGSFDVDNVSN            49     TBP2-2          231-261                LEGGFYGPKGEELGFRFLAGDKVVFGVFSAK                                          50     TBP2-3          358-380                TVGKKTYQVEACCSNLSYVKFGM   51     TBP2-4          527-549                ATVKGAFYGPKASELGGYFTYNG   52     TBP2-5           1-36 MKLAALNLFDRNKPSLLNEDSYMIFSSRSTIEEDV                                          53     TBP2-6          29-64 STIEEDVKNDNQNGEHPIDSIVDPRAPNSNENRHG                                          54     TBP2-7          57-92 SNENRHGQKYVYSGLYYIQSWSLRDLPNKKFYSGY                                          55     TBP2-8           85-120                KKFYSGYYGYAYYFGNTTASALPVGGVATYKGTWS                                          56     TBP2-9          113-148                TYKGTWSFITAAENGKNYELLRNSGGGQAYSRRSA                                          57     TBP2-10          141-176                AYSRRSATPEDIDLDRKTGLTSEFTVNFGTKKLTG                                          58     TBP2-11          169-204                GTKKLTGGLYYNLRETDANKSQNRTHKLYDLRADV                                          59     TBP2-12          197-232                YDLEADVHSNRFRGKVKPTKKESSEEHPFTSEGTL                                          60     TBP2-13          225-260                FTSEGTLEGGFYGPEGQELGGKFLAHDKKVLGVFS                                          61     TBP2-14          253-288                KVLGVFSAKEQQETSENKKLPKETLIDGKLTTFKT                                          62     TBP2-15          281-316                KLTTFKTTNATANATTDATTSTTASTKTDTTTNAT                                          63     TBP2-16          309-344                DTTTNATATTENFTTKDIPSLGEADYLLIDNYPVP                                          64     TBP2-17          337-372                IDNYPVPLFPESGDFISSKHHTVGKKTYQVEACCS                                          65     TBP2-M          360-406                CSNLSYVKGFGMYYEAPPKEEEKEKEKDKDKEKEKQA                                          66     TBP2-19          393-428                KEKDKDKEKEKQATTSIKTTYQFLLGLRTPSSEIP                                          67     TBP2-20          421-456                TPSSEIPKEGSAKYHGNWFGYISDGETSYSASGDK                                          68     TBP2-21          449-484                YSASGDKERSKNAVAEFNVNFAEKTLTGELKRHDT                                          69     TBP2-22          477-512                ELKRHDTQNPVFKINATFQSGKNDFTGTATAKDLA                                          70     TBP2-23          505-540                ATAKDLAIDGKNTQGTSKVNFTATVNGAFYGPHAT                                          71     TBP2-24          533-559                FYGPHATELGGYFTYNGNNPTDKNSS                                          72     TBP2-C          553-581                CPTDKNSSSNSEKARAAVVFGAKKQQVETTK                                          73     TBP2-25          231-238                LEGGFYGP                  74     TBP2-26          18-25 CSGGGSFD                  75     TBP2-27          130-134                YVYSGL                    76     TBP2-2B          345-355                CCSNLSYVKFG               77     TBP2-29          401-407                FLLGHRT                   78     TBP2-30          450-456                EFNVDF                    79     TBP2-31          485-491                NAFTGTA                   80     TBP2-32          516-522                VNGAFYG                   81     TBP2-33          527-532                ELGGYF                    82     TBP2-34          562-566                VVFGAR                    83     TBP2-35          562-568                VVFGAK                    84     TBP2-36          231-238                LEGGFYG                   85     __________________________________________________________________________      .sup.1 Residue number from the sequence of Tbp2 of H. influenzae type B      Eagan strain (as shown in FIG. 9).

                                      TABLE 4     __________________________________________________________________________     Guinea pig antibody responses to Tbp1 and Tbp2 peptides     PEPTIDE          SEQ ID              SEQUENCES                TITRE     __________________________________________________________________________     TBP1-N          13  AETQSIKDTKEAISSEVDTQSTEDSELETISVTAEK                                       500     TBP1-M          30  TASSISEKRGEARRNGLQSSPYLYPTPKAELVGGDLC                                       1562500     TBP1-1          46  AETQSIKDTKEAISC          <100     TBP2-1          49  CSGGGSFDVDNVSN           2500     TBP2-2          50  LEGGFYGPKGEELGFRFLAGDKKVFGVFSAK                                       12500     TBP2-3          51  TVGKKTYQVEACCSNLSYVKFGM  62500     TBP2-4          52  ATVKGAFYGPKASELGGYFTYNG  <100     TBP2-M          66  CSNLSYVKFGMYYEAPPKEEEKEKEKDKDKEKEKQA                                       62500     TBP2-C          73  CPTDKNSSSNSEKARAAVVFGAKKQQVETTK                                       312500     __________________________________________________________________________

                                      TABLE 5     __________________________________________________________________________     Neutralizing activity of anti-Tbp2 and anti-peptide sera     against polio/Tbp2 hybrid viruses              Neutralizing Titre v. Virus.sup.b     Sera.sup.a              PV1TBP2A                      PV1TBP2B                            PV1TBP2C                                  PV1TBP2D                                        PV1XLD     __________________________________________________________________________     Rb @ PV1 >40,9600                      25,844                            20,480                                  16,763                                        >40,960     Rb 516 D0              <4      <4    <4    <4    <4     RB 516 D42              40      20    <4    <4    <4     GP561, 562 D0 pool              <4      <4    <4    <4    <4     GP 561 D56              >2048   >2048 >2048 1164  <4     GP 562 D56              >2048   >2048 25    10    <4     GP558, 559, 560              <4      <4    <4    <4    <4     D56 pool     __________________________________________________________________________      .sup.a Rb @ PV1 is pool of rabbit immune sera raised against PV1XLD.      Rabbit 516 was immunised with three successive 3 μg doses of      recombinant H. influenzae DL63 transferrin binding protein 2 on days 1, 1      and 28. Serum was collected on days 0 (D0) and 42 (D42). Guineapigs were      immunized with four successive doses of 200 μg of peptide on days 1,      14, 28 and 42. Sera were collected on day 0 (D0) and day 56 (D56).      GuineaPigs 561 and 562 received a peptide containing  #the sequence      LEGGFYGP (SEQ ID NO: 74). Guineapigs 558, 559 and 556 received a control      peptide with an unrelated sequence.      .sup.b Titre is the inverse dilution of serum giving a 50% endpoint in a      virus neutralization assay versus 100 TCID.sub.50 of virus.

                  TABLE 6     ______________________________________     Peptide-specific IgG titres of rabbits immunised with     PV1TBP2A or PV1TBP2B                    PEPTIDE-SPECIFIC                    IgG TITRES.sup.a     RABBIT (ANTIGEN) PREBLEED  DAY 27     ______________________________________     40 (PV1TBP2A)    <20       640     41 (PV1TBP2A)    <20       640     42 (PV1TBP2A)    <20       2560     43 (PV1TBP2B)    <20       160     44 (PV1TBP2B)    <20       1280     45 (PV1TBP2B)    <20       1280     10 (PV1 Mahoney)           <20.sup.b     11 (PV1 Mahoney)           <20     ______________________________________      .sup.a Titres are the reciprocal of the greatest dilution of sera giving      an A.sub.450 of at least twice the background value. The background value      was the mean A.sub.450 of wells assayed in the absence of rabbit sera.      .sup.b Titres for rabbits 10 and 11 refer to sera taken on day 42 after      three immunisations with PV1 Mahoney. Rabbits 10 and 11 were immunised as      rabbits 40 to 45, except that an additional booster dose was administered      on day 28.

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WO

    __________________________________________________________________________     #             SEQUENCE LISTING     - (1) GENERAL INFORMATION:     -    (iii) NUMBER OF SEQUENCES: 147     - (2) INFORMATION FOR SEQ ID NO:1:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 4699 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: double               (D) TOPOLOGY: linear     -     (ix) FEATURE:               (A) NAME/KEY: CDS               (B) LOCATION: join(10..194 - #0, 1957..4696)     #ID NO:1: (xi) SEQUENCE DESCRIPTION: SEQ     - TATAACTCA ATG AAA TCT GTA CCT CTT ATC TCT GGT - # GGA CTT TCC TTT       48     #Leu Ile Ser Gly Gly Leu Ser Phe     #         10     - TTA CTA AGT GCT TGT AGC GGA GGG GGG TCT TT - #T GAT GTA GAT AAC GTC       96     Leu Leu Ser Ala Cys Ser Gly Gly Gly Ser Ph - #e Asp Val Asp Asn Val     #     25     - TCT AAT ACC CCC TCT TCT AAA CCA CGT TAT CA - #A GAC GAT ACT TCA AGT      144     Ser Asn Thr Pro Ser Ser Lys Pro Arg Tyr Gl - #n Asp Asp Thr Ser Ser     # 45     - TCA AGA ACA AAA TCT AAA TTG GAA AAG TTG TC - #C ATT CCT TCT TTA GGG      192     Ser Arg Thr Lys Ser Lys Leu Glu Lys Leu Se - #r Ile Pro Ser Leu Gly     #                 60     - GGA GGG ATG AAG TTA GCG GCT CTG AAT CTT TT - #T GAT AGG AAC AAA CCT      240     Gly Gly Met Lys Leu Ala Ala Leu Asn Leu Ph - #e Asp Arg Asn Lys Pro     #             75     - AGT CTC TTA AAT GAA GAT AGC TAT ATG ATA TT - #T TCC TCA CGT TCT ACG      288     Ser Leu Leu Asn Glu Asp Ser Tyr Met Ile Ph - #e Ser Ser Arg Ser Thr     #         90     - ATT GAA GAG GAT GTT AAA AAT GAC AAT CAA AA - #C GGC GAG CAC CCT ATT      336     Ile Glu Glu Asp Val Lys Asn Asp Asn Gln As - #n Gly Glu His Pro Ile     #    105     - GAC TCA ATA GTC GAT CCT AGA GCA CCA AAT TC - #A AAC GAA AAT CGT CAT      384     Asp Ser Ile Val Asp Pro Arg Ala Pro Asn Se - #r Asn Glu Asn Arg His     110                 1 - #15                 1 - #20                 1 -     #25     - GGA CAA AAA TAT GTA TAT TCA GGG CTT TAT TA - #T ATT CAA TCG TGG AGT      432     Gly Gln Lys Tyr Val Tyr Ser Gly Leu Tyr Ty - #r Ile Gln Ser Trp Ser     #               140     - CTA AGA GAT TTA CCA AAT AAA AAG TTT TAT TC - #A GGT TAC TAT GGA TAT      480     Leu Arg Asp Leu Pro Asn Lys Lys Phe Tyr Se - #r Gly Tyr Tyr Gly Tyr     #           155     - GCG TAT TAC TTT GGC AAT ACA ACT GCC TCT GC - #A TTA CCT GTA GGT GGC      528     Ala Tyr Tyr Phe Gly Asn Thr Thr Ala Ser Al - #a Leu Pro Val Gly Gly     #       170     - GTA GCA ACG TAT AAA GGA ACT TGG AGC TTC AT - #C ACC GCA GCT GAA AAT      576     Val Ala Thr Tyr Lys Gly Thr Trp Ser Phe Il - #e Thr Ala Ala Glu Asn     #   185     - GGC AAG AAT TAT GAA TTG TTA AGA AAT TCT GG - #T GGC GGT CAA GCT TAT      624     Gly Lys Asn Tyr Glu Leu Leu Arg Asn Ser Gl - #y Gly Gly Gln Ala Tyr     190                 1 - #95                 2 - #00                 2 -     #05     - TCT CGA CGT AGT GCT ACT CCA GAA GAT ATT GA - #T TTA GAT CGT AAG ACG      672     Ser Arg Arg Ser Ala Thr Pro Glu Asp Ile As - #p Leu Asp Arg Lys Thr     #               220     - GGC TTA ACA AGT GAA TTT ACT GTC AAT TTT GG - #T ACA AAA AAG CTC ACT      720     Gly Leu Thr Ser Glu Phe Thr Val Asn Phe Gl - #y Thr Lys Lys Leu Thr     #           235     - GGA GGA CTT TAT TAT AAT TTA CGT GAA ACA GA - #T GCT AAT AAA TCA CAA      768     Gly Gly Leu Tyr Tyr Asn Leu Arg Glu Thr As - #p Ala Asn Lys Ser Gln     #       250     - AAT AGA ACA CAT AAA CTC TAC GAT CTA GAA GC - #T GAT GTT CAT AGC AAC      816     Asn Arg Thr His Lys Leu Tyr Asp Leu Glu Al - #a Asp Val His Ser Asn     #   265     - CGA TTC AGG GGT AAA GTA AAG CCA ACC AAA AA - #A GAG TCT TCT GAA GAA      864     Arg Phe Arg Gly Lys Val Lys Pro Thr Lys Ly - #s Glu Ser Ser Glu Glu     270                 2 - #75                 2 - #80                 2 -     #85     - CAT CCC TTT ACC AGC GAG GGA ACA TTA GAA GG - #T GGT TTT TAC GGG CCT      912     His Pro Phe Thr Ser Glu Gly Thr Leu Glu Gl - #y Gly Phe Tyr Gly Pro     #               300     - GAG GGT CAA GAA TTA GGA GGA AAG TTT TTA GC - #T CAC GAC AAA AAA GTT      960     Glu Gly Gln Glu Leu Gly Gly Lys Phe Leu Al - #a His Asp Lys Lys Val     #           315     - TTG GGG GTA TTT AGT GCC AAA GAA CAG CAA GA - #A ACG TCA GAA AAC AAA     1008     Leu Gly Val Phe Ser Ala Lys Glu Gln Gln Gl - #u Thr Ser Glu Asn Lys     #       330     - AAA TTA CCC AAA GAA ACC TTA ATT GAT GGC AA - #G CTA ACT ACT TTT AAA     1056     Lys Leu Pro Lys Glu Thr Leu Ile Asp Gly Ly - #s Leu Thr Thr Phe Lys     #   345     - ACA ACC AAT GCA ACA GCC AAT GCA ACA ACC GA - #T GCA ACA ACC AGT ACA     1104     Thr Thr Asn Ala Thr Ala Asn Ala Thr Thr As - #p Ala Thr Thr Ser Thr     350                 3 - #55                 3 - #60                 3 -     #65     - ACA GCC AGT ACA AAA ACC GAT ACA ACA ACC AA - #T GCA ACA GCC AAT ACA     1152     Thr Ala Ser Thr Lys Thr Asp Thr Thr Thr As - #n Ala Thr Ala Asn Thr     #               380     - GAA AAC TTT ACG ACA AAA GAT ATA CCA AGT TT - #G GGT GAA GCT GAT TAT     1200     Glu Asn Phe Thr Thr Lys Asp Ile Pro Ser Le - #u Gly Glu Ala Asp Tyr     #           395     - CTT TTA ATT GAT AAT TAC CCT GTT CCT CTT TT - #C CCT GAG AGT GGT GAT     1248     Leu Leu Ile Asp Asn Tyr Pro Val Pro Leu Ph - #e Pro Glu Ser Gly Asp     #       410     - TTC ATA AGT AGT AAG CAC CAT ACT GTA GGA AA - #G AAA ACC TAT CAA GTA     1296     Phe Ile Ser Ser Lys His His Thr Val Gly Ly - #s Lys Thr Tyr Gln Val     #   425     - GAA GCA TGT TGC AGT AAT CTA AGC TAT GTA AA - #A TTT GGT ATG TAT TAT     1344     Glu Ala Cys Cys Ser Asn Leu Ser Tyr Val Ly - #s Phe Gly Met Tyr Tyr     430                 4 - #35                 4 - #40                 4 -     #45     - GAA GCC CCA CCT AAA GAA GAA GAA AAA GAA AA - #A GAA AAA GAC AAA GAC     1392     Glu Ala Pro Pro Lys Glu Glu Glu Lys Glu Ly - #s Glu Lys Asp Lys Asp     #               460     - AAA GAA AAA GAA AAA CAA GCG ACA ACA TCT AT - #C AAG ACT TAT TAT CAA     1440     Lys Glu Lys Glu Lys Gln Ala Thr Thr Ser Il - #e Lys Thr Tyr Tyr Gln     #           475     - TTC TTA TTA GGT CTC CGT ACT CCC AGT TCT GA - #A ATA CCT AAA GAA GGA     1488     Phe Leu Leu Gly Leu Arg Thr Pro Ser Ser Gl - #u Ile Pro Lys Glu Gly     #       490     - AGT GCA AAA TAT CAT GGT AAT TGG TTT GGT TA - #T ATT AGT GAT GGC GAG     1536     Ser Ala Lys Tyr His Gly Asn Trp Phe Gly Ty - #r Ile Ser Asp Gly Glu     #   505     - ACA TCT TAC TCC GCC AGT GGT GAT AAG GAA CG - #C AGT AAA AAT GCT GTC     1584     Thr Ser Tyr Ser Ala Ser Gly Asp Lys Glu Ar - #g Ser Lys Asn Ala Val     510                 5 - #15                 5 - #20                 5 -     #25     - GCC GAG TTT AAT GTA AAT TTT GCC GAG AAA AC - #A TTA ACA GGC GAA TTA     1632     Ala Glu Phe Asn Val Asn Phe Ala Glu Lys Th - #r Leu Thr Gly Glu Leu     #               540     - AAA CGA CAC GAT ACT CAA AAT CCC GTA TTT AA - #A ATT AAT GCA ACC TTT     1680     Lys Arg His Asp Thr Gln Asn Pro Val Phe Ly - #s Ile Asn Ala Thr Phe     #           555     - CAA AGT GGT AAG AAT GAC TTC ACT GGT ACA GC - #A ACC GCA AAA GAT TTA     1728     Gln Ser Gly Lys Asn Asp Phe Thr Gly Thr Al - #a Thr Ala Lys Asp Leu     #       570     - GCA ATA GAT GGT AAA AAT ACA CAA GGC ACA TC - #T AAA GTC AAT TTC ACG     1776     Ala Ile Asp Gly Lys Asn Thr Gln Gly Thr Se - #r Lys Val Asn Phe Thr     #   585     - GCA ACA GTA AAC GGG GCA TTT TAT GGT CCG CA - #C GCT ACA GAA TTA GGC     1824     Ala Thr Val Asn Gly Ala Phe Tyr Gly Pro Hi - #s Ala Thr Glu Leu Gly     590                 5 - #95                 6 - #00                 6 -     #05     - GGT TAT TTC ACC TAT AAC GGA AAC AAT CCT AC - #A GAT AAA AAT TCA TCA     1872     Gly Tyr Phe Thr Tyr Asn Gly Asn Asn Pro Th - #r Asp Lys Asn Ser Ser     #               620     - TCC AAT TCA GAA AAG GCA AGA GCT GCC GTT GT - #G TTT GGA GCT AAA AAA     1920     Ser Asn Ser Glu Lys Ala Arg Ala Ala Val Va - #l Phe Gly Ala Lys Lys     #           635     - CAA CAA GTA GAA ACA ACC  AA  GTAATGGAAT AC - #TAAA A ATG ACT AAA AAA     1969     #Lys Lys        Met Thr  Lys     #          645     - CCC TAT TTT CGC CTA AGT ATT ATT TCT TGT CT - #T TTA ATT TCA TGC TAT     2017     Pro Tyr Phe Arg Leu Ser Ile Ile Ser Cys Le - #u Leu Ile Ser Cys Tyr     #   660     - GTA AAA GCA GAA ACT CAA AGT ATA AAA GAT AC - #A AAA GAA GCT ATA TCA     2065     Val Lys Ala Glu Thr Gln Ser Ile Lys Asp Th - #r Lys Glu Ala Ile Ser     665                 6 - #70                 6 - #75                 6 -     #80     - TCT GAA GTG GAC ACT CAA AGT ACA GAA GAT TC - #A GAA TTA GAA ACT ATC     2113     Ser Glu Val Asp Thr Gln Ser Thr Glu Asp Se - #r Glu Leu Glu Thr Ile     #               695     - TCA GTC ACT GCA GAA AAA GTT AGA GAT CGT AA - #A GAT AAT GAA GTA ACT     2161     Ser Val Thr Ala Glu Lys Val Arg Asp Arg Ly - #s Asp Asn Glu Val Thr     #           710     - GGA CTT GGC AAA ATT ATA AAA ACT AGT GAA AG - #T ATC AGC CGA GAA CAA     2209     Gly Leu Gly Lys Ile Ile Lys Thr Ser Glu Se - #r Ile Ser Arg Glu Gln     #       725     - GTA TTA AAT ATT CGT GAT CTA ACA CGC TAT GA - #T CCA GGG ATT TCA GTT     2257     Val Leu Asn Ile Arg Asp Leu Thr Arg Tyr As - #p Pro Gly Ile Ser Val     #   740     - GTA GAA CAA GGT CGC GGT GCA AGT TCT GGA TA - #T TCT ATT CGT GGT ATG     2305     Val Glu Gln Gly Arg Gly Ala Ser Ser Gly Ty - #r Ser Ile Arg Gly Met     745                 7 - #50                 7 - #55                 7 -     #60     - GAC AGA AAT AGA GTT GCT TTA TTA GTA GAT GG - #T TTA CCT CAA ACG CAA     2353     Asp Arg Asn Arg Val Ala Leu Leu Val Asp Gl - #y Leu Pro Gln Thr Gln     #               775     - TCT TAT GTA GTG CAA AGC CCT TTA GTT GCT CG - #T TCA GGA TAT TCT GGC     2401     Ser Tyr Val Val Gln Ser Pro Leu Val Ala Ar - #g Ser Gly Tyr Ser Gly     #           790     - ACT GGT GCA ATT AAT GAA ATT GAA TAT GAA AA - #T GTA AAG GCC GTC GAA     2449     Thr Gly Ala Ile Asn Glu Ile Glu Tyr Glu As - #n Val Lys Ala Val Glu     #       805     - ATA AGC AAG GGG GGG AGT TCT TCT GAG TAT GG - #T AAT GGA GCA CTA GCT     2497     Ile Ser Lys Gly Gly Ser Ser Ser Glu Tyr Gl - #y Asn Gly Ala Leu Ala     #   820     - GGT TCT GTA ACA TTT CAA AGC AAA TCA GCA GC - #C GAT ATC TTA GAA GGA     2545     Gly Ser Val Thr Phe Gln Ser Lys Ser Ala Al - #a Asp Ile Leu Glu Gly     825                 8 - #30                 8 - #35                 8 -     #40     - GAC AAA TCA TGG GGA ATT CAA ACT AAA AAT GC - #T TAT TCA AGC AAA AAT     2593     Asp Lys Ser Trp Gly Ile Gln Thr Lys Asn Al - #a Tyr Ser Ser Lys Asn     #               855     - AAA GGC TTT ACC CAT TCT TTA GCT GTA GCA GG - #A AAA CAA GGT GGA TTT     2641     Lys Gly Phe Thr His Ser Leu Ala Val Ala Gl - #y Lys Gln Gly Gly Phe     #           870     - GAA GGG GTC GCC ATT TAC ACT CAC CGA AAT TC - #A ATT GAA ACC CAA GTC     2689     Glu Gly Val Ala Ile Tyr Thr His Arg Asn Se - #r Ile Glu Thr Gln Val     #       885     - CAT AAA GAT GCA TTA AAA GGC GTG CAA AGT TA - #T GAT CGA TTC ATC GCC     2737     His Lys Asp Ala Leu Lys Gly Val Gln Ser Ty - #r Asp Arg Phe Ile Ala     #   900     - ACA ACA GAG GAT CAA TCT GCA TAC TTT GTG AT - #G CAA GAT GAG TGT CTA     2785     Thr Thr Glu Asp Gln Ser Ala Tyr Phe Val Me - #t Gln Asp Glu Cys Leu     905                 9 - #10                 9 - #15                 9 -     #20     - GAT GGT TAT GAC AAG TGT AAA ACT TCA CCC AA - #A CGA CCT GCG ACT TTA     2833     Asp Gly Tyr Asp Lys Cys Lys Thr Ser Pro Ly - #s Arg Pro Ala Thr Leu     #               935     - TCC ACC CAA AGA GAA ACC GTA AGC GTT TCA GA - #T TAT ACG GGG GCT AAC     2881     Ser Thr Gln Arg Glu Thr Val Ser Val Ser As - #p Tyr Thr Gly Ala Asn     #           950     - CGT ATC AAA CCT AAT CCA ATG AAA TAT GAA AG - #C CAG TCT TGG TTT TTA     2929     Arg Ile Lys Pro Asn Pro Met Lys Tyr Glu Se - #r Gln Ser Trp Phe Leu     #       965     - AGA GGA GGT TAT CAT TTT TCT GAA CAA CAC TA - #T ATT GGT GGT ATT TTT     2977     Arg Gly Gly Tyr His Phe Ser Glu Gln His Ty - #r Ile Gly Gly Ile Phe     #   980     - GAA TTC ACA CAA CAA AAA TTT GAT ATC CGT GA - #T ATG ACA TTT CCC GCT     3025     Glu Phe Thr Gln Gln Lys Phe Asp Ile Arg As - #p Met Thr Phe Pro Ala     985                 9 - #90                 9 - #95                 1 -     #000     - TAT TTA AGG CCA ACA GAA GAC AAG GAT TTA CA - #A AGT CGC CCT TTT TAT     3073     Tyr Leu Arg Pro Thr Glu Asp Lys Asp Leu Gl - #n Ser Arg Pro Phe Tyr     #              10150     - CCA AAG CAA GAT TAT GGT GCA TAT CAA CAT AT - #T GGT GAT GGC AGA GGC     3121     Pro Lys Gln Asp Tyr Gly Ala Tyr Gln His Il - #e Gly Asp Gly Arg Gly     #          10305     - GTT AAA TAT GCA AGT GGG CTT TAT TTC GAT GA - #A CAC CAT AGA AAA CAG     3169     Val Lys Tyr Ala Ser Gly Leu Tyr Phe Asp Gl - #u His His Arg Lys Gln     #      10450     - CGT GTA GGT ATT GAA TAT ATT TAC GAA AAT AA - #G AAC AAA GCG GGC ATC     3217     Arg Val Gly Ile Glu Tyr Ile Tyr Glu Asn Ly - #s Asn Lys Ala Gly Ile     #  10605     - ATT GAC AAA GCG GTG TTA AGT GCT AAT CAA CA - #A ACA TCA TAC TTG ACA     3265     Ile Asp Lys Ala Val Leu Ser Ala Asn Gln Gl - #n Thr Ser Tyr Leu Thr     #               10801070 - #                1075     - GTT ATA TGC GAC ATA CGC ATT GCA GTC TTT AT - #C CAT AAT CCA AGT AAG     3313     Val Ile Cys Asp Ile Arg Ile Ala Val Phe Il - #e His Asn Pro Ser Lys     #              10950     - AAT TGC CGC CCA ACA CTT GAT AAA CCT TAT TC - #A TAC TAT CAT TCT GAT     3361     Asn Cys Arg Pro Thr Leu Asp Lys Pro Tyr Se - #r Tyr Tyr His Ser Asp     #          11105     - AGA AAT GTT TAT AAA GAA AAA CAT AAC ATG TT - #G CAA TTG AAT TTA GAG     3409     Arg Asn Val Tyr Lys Glu Lys His Asn Met Le - #u Gln Leu Asn Leu Glu     #      11250     - AAA AAA ATT CAA CAA AAT TGG CTT ACT CAT CA - #A ATT GCC TTC AAT CTT     3457     Lys Lys Ile Gln Gln Asn Trp Leu Thr His Gl - #n Ile Ala Phe Asn Leu     #  11405     - GGT TTT GAT GAC TTT ACT TCC GCA CTT CAG CA - #T AAA GAT TAT TTA ACT     3505     Gly Phe Asp Asp Phe Thr Ser Ala Leu Gln Hi - #s Lys Asp Tyr Leu Thr     #               11601150 - #                1155     - CGA CGT GTT ATC GCT ACG GCA AGT AGT ATT TC - #A GAG AAA CGT GGT GAA     3553     Arg Arg Val Ile Ala Thr Ala Ser Ser Ile Se - #r Glu Lys Arg Gly Glu     #              11750     - GCA AGA AGA AAT GGT TTA CAA TCA AGT CCT TA - #C TTA TAC CCA ACA CCA     3601     Ala Arg Arg Asn Gly Leu Gln Ser Ser Pro Ty - #r Leu Tyr Pro Thr Pro     #          11905     - AAA GCA GAG TTG GTA GGA GGA GAT CTT TGT AA - #T TAT CAA GGT AAG TCC     3649     Lys Ala Glu Leu Val Gly Gly Asp Leu Cys As - #n Tyr Gln Gly Lys Ser     #      12050     - TCT AAT TAC AGT GAC TGT AAA GTG CGG TTA AT - #T AAA GGG AAA AAT TAT     3697     Ser Asn Tyr Ser Asp Cys Lys Val Arg Leu Il - #e Lys Gly Lys Asn Tyr     #  12205     - TAT TTC GCA GCA CGC AAT AAT ATG GCA TTA GG - #G AAA TAC GTT GAT TTA     3745     Tyr Phe Ala Ala Arg Asn Asn Met Ala Leu Gl - #y Lys Tyr Val Asp Leu     #               12401230 - #                1235     - GGT TTA GGT ATG AGG TAT GAC GTA TCT CGT AC - #A AAA GCT AAT GAA TCA     3793     Gly Leu Gly Met Arg Tyr Asp Val Ser Arg Th - #r Lys Ala Asn Glu Ser     #              12550     - ACT ATT AGT GTT GGT AAA TTT AAA AAT TTC TC - #T TGG AAT ACT GGT ATT     3841     Thr Ile Ser Val Gly Lys Phe Lys Asn Phe Se - #r Trp Asn Thr Gly Ile     #          12705     - GTC ATA AAA CCA ACG GAA TGG CTT GAT CTT TC - #T TAT CGC CTT TCT ACT     3889     Val Ile Lys Pro Thr Glu Trp Leu Asp Leu Se - #r Tyr Arg Leu Ser Thr     #      12850     - GGA TTT AGA AAT CCT AGT TTT GCT GAA ATG TA - #T GGT TGG CGG TAT GGT     3937     Gly Phe Arg Asn Pro Ser Phe Ala Glu Met Ty - #r Gly Trp Arg Tyr Gly     #  13005     - GGC AAG GAT ACC GAT GTT TAT ATA GGT AAA TT - #T AAG CCT GAA ACA TCT     3985     Gly Lys Asp Thr Asp Val Tyr Ile Gly Lys Ph - #e Lys Pro Glu Thr Ser     #               13201310 - #                1315     - CGT AAC CAA GAG TTT GGT CTC GCT CTA AAA GG - #G GAT TTT GGT AAT ATT     4033     Arg Asn Gln Glu Phe Gly Leu Ala Leu Lys Gl - #y Asp Phe Gly Asn Ile     #              13350     - GAG ATC AGT CAT TTT AGT AAT GCT TAT CGA AA - #T CTT ATC GCC TTT GCT     4081     Glu Ile Ser His Phe Ser Asn Ala Tyr Arg As - #n Leu Ile Ala Phe Ala     #          13505     - GAA GAA CTT AGT AAA AAT GGA ACT ACT GGA AA - #G GGC AAT TAT GGA TAT     4129     Glu Glu Leu Ser Lys Asn Gly Thr Thr Gly Ly - #s Gly Asn Tyr Gly Tyr     #      13650     - CAT AAT GCA CAA AAT GCA AAA TTA GTT GGC GT - #A AAT ATA ACT GCG CAA     4177     His Asn Ala Gln Asn Ala Lys Leu Val Gly Va - #l Asn Ile Thr Ala Gln     #  13805     - TTA GAT TTT AAT GGT TTA TGG AAA CGT ATT CC - #C TAC GGT TGG TAT GCA     4225     Leu Asp Phe Asn Gly Leu Trp Lys Arg Ile Pr - #o Tyr Gly Trp Tyr Ala     #               14001390 - #                1395     - ACA TTT GCT TAT AAC CGA GTA AAA GTT AAA GA - #T CAA AAA ATC AAT GCT     4273     Thr Phe Ala Tyr Asn Arg Val Lys Val Lys As - #p Gln Lys Ile Asn Ala     #              14150     - GGT TTA GCT TCC GTA AGC AGT TAT TTA TTT GA - #T GCC ATT CAG CCC AGC     4321     Gly Leu Ala Ser Val Ser Ser Tyr Leu Phe As - #p Ala Ile Gln Pro Ser     #          14305     - CGT TAT ATC ATT GGT TTA GGC TAT GAT CAT CC - #A AGT AAT ACT TGG GGA     4369     Arg Tyr Ile Ile Gly Leu Gly Tyr Asp His Pr - #o Ser Asn Thr Trp Gly     #      14450     - ATT AAG ACA ATG TTT ACT CAA TCA AAA GCA AA - #A TCT CAA AAT GAA TTG     4417     Ile Lys Thr Met Phe Thr Gln Ser Lys Ala Ly - #s Ser Gln Asn Glu Leu     #  14605     - CTA GGA AAA CGT GCA TTG GGT AAC AAT TCA AG - #G AAT GTA AAA TCA ACA     4465     Leu Gly Lys Arg Ala Leu Gly Asn Asn Ser Ar - #g Asn Val Lys Ser Thr     #               14801470 - #                1475     - AGA AAA CTT ACT CGG GCA TGG CAT ATC TTA GA - #T GTA TCG GGT TAT TAC     4513     Arg Lys Leu Thr Arg Ala Trp His Ile Leu As - #p Val Ser Gly Tyr Tyr     #              14950     - ATG GTG AAT AGA AGT ATT TTG TTC CGA TTA GG - #A GTA TAT AAT TTA TTA     4561     Met Val Asn Arg Ser Ile Leu Phe Arg Leu Gl - #y Val Tyr Asn Leu Leu     #          15105     - AAC TAT CGC TAT GTC ACT TGG GAA GCG GTG CG - #T CAA ACA GCA CAA GGT     4609     Asn Tyr Arg Tyr Val Thr Trp Glu Ala Val Ar - #g Gln Thr Ala Gln Gly     #      15250     - GCG GTC AAT CAA CAT CAA AAT GTT GGT AAC TA - #T ACT CGC TAC GCA GCA     4657     Ala Val Asn Gln His Gln Asn Val Gly Asn Ty - #r Thr Arg Tyr Ala Ala     #  15405     - TCA GGA CGA AAC TAT ACC TTA ACA TTA GAA AT - #G AAA TTC TAA     #4699     Ser Gly Arg Asn Tyr Thr Leu Thr Leu Glu Me - #t Lys Phe     1545                1550 - #                1555     - (2) INFORMATION FOR SEQ ID NO:2:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 5033 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: double               (D) TOPOLOGY: linear     -     (ix) FEATURE:               (A) NAME/KEY: CDS               (B) LOCATION: join(169..21 - #48, 2165..4900)     #ID NO:2: (xi) SEQUENCE DESCRIPTION: SEQ     - GCCCAAGCTA CATTGGTTAA TGATAAGCCT ATAAATGATA AGAAAGAAAT TT - #GTTTTACG       60     - CCATTTTTCA TATTTTATCC ATGAACTTAA AAAACTCTAA CTTGACATTA TT - #ACAAAAAA      120     #AAA TCT     177GAATTAT TATCAATTTT GTATGAGTAT ATAATTCT ATG     #                 Met - # Lys Ser     # 1     - GTA CCT CTT ATC TCT GGT GGA CTT TCC TTT TT - #A CTA AGT GCT TGT AGC      225     Val Pro Leu Ile Ser Gly Gly Leu Ser Phe Le - #u Leu Ser Ala Cys Ser     #      15     - GGA GGG GGG TCT TTT GAT GTA GAT AAC GTC TC - #T AAT ACC CCC TCT TCT      273     Gly Gly Gly Ser Phe Asp Val Asp Asn Val Se - #r Asn Thr Pro Ser Ser     # 35     - AAA CCA CGT TAT CAA GAC GAT ACC TCG AAT CA - #A AGA AAA AAA TCT AAT      321     Lys Pro Arg Tyr Gln Asp Asp Thr Ser Asn Gl - #n Arg Lys Lys Ser Asn     #                 50     - TTG AAA AAG TTG TTC ATT CCT TCT TTA GGA GG - #A GGG ATG AAA TTG GTG      369     Leu Lys Lys Leu Phe Ile Pro Ser Leu Gly Gl - #y Gly Met Lys Leu Val     #             65     - GCT CAG AAT CTT CGT GGT AAT AAA GAA CCT AG - #T TTC TTA AAT GAA GAT      417     Ala Gln Asn Leu Arg Gly Asn Lys Glu Pro Se - #r Phe Leu Asn Glu Asp     #         80     - GAC TAT ATA TCA TAT TTT TCC TCA CTT TCT AC - #G ATT GAA AAG GAT GTT      465     Asp Tyr Ile Ser Tyr Phe Ser Ser Leu Ser Th - #r Ile Glu Lys Asp Val     #     95     - AAA GAT AAC AAT AAA AAC GGG GCG GAC CTT AT - #T GGC TCA ATA GAC GAG      513     Lys Asp Asn Asn Lys Asn Gly Ala Asp Leu Il - #e Gly Ser Ile Asp Glu     100                 1 - #05                 1 - #10                 1 -     #15     - CCT AGT ACA ACA AAT CCA CCC GAA AAG CAT CA - #T GGA CAA AAA TAT GTA      561     Pro Ser Thr Thr Asn Pro Pro Glu Lys His Hi - #s Gly Gln Lys Tyr Val     #               130     - TAT TCA GGG CTT TAT TAT ACT CCA TCG TGG AG - #T TTA AAC GAT TCT AAA      609     Tyr Ser Gly Leu Tyr Tyr Thr Pro Ser Trp Se - #r Leu Asn Asp Ser Lys     #           145     - AAC AAG TTT TAT TTA GGT TAC TAT GGA TAT GC - #G TTT TAT TAT GGT AAT      657     Asn Lys Phe Tyr Leu Gly Tyr Tyr Gly Tyr Al - #a Phe Tyr Tyr Gly Asn     #       160     - AAA ACT GCA ACA AAC TTG CCA GTA AAC GGT GT - #A GCT AAA TAC AAA GGA      705     Lys Thr Ala Thr Asn Leu Pro Val Asn Gly Va - #l Ala Lys Tyr Lys Gly     #   175     - ACT TGG GAT TTC ATC ACT GCA ACT AAA AAT GG - #C AAA CGT TAT CCT TTG      753     Thr Trp Asp Phe Ile Thr Ala Thr Lys Asn Gl - #y Lys Arg Tyr Pro Leu     180                 1 - #85                 1 - #90                 1 -     #95     - TTA AGT AAT GGC AGT CAC GCT TAT TAT CGA CG - #T AGT GCA ATT CCA GAA      801     Leu Ser Asn Gly Ser His Ala Tyr Tyr Arg Ar - #g Ser Ala Ile Pro Glu     #               210     - GAT ATT GAT TTA GAA AAT GAT TCA AAG AAT GG - #T GAT ATA GGC TTA ATA      849     Asp Ile Asp Leu Glu Asn Asp Ser Lys Asn Gl - #y Asp Ile Gly Leu Ile     #           225     - AGT GAA TTT AGT GCA GAT TTT GGG ACT AAA AA - #A CTG ACA GGA CAA CTG      897     Ser Glu Phe Ser Ala Asp Phe Gly Thr Lys Ly - #s Leu Thr Gly Gln Leu     #       240     - TCT TAC ACC AAA AGA AAA ACT AAT AAT CAA CC - #A TAT GAA AAG AAA AAA      945     Ser Tyr Thr Lys Arg Lys Thr Asn Asn Gln Pr - #o Tyr Glu Lys Lys Lys     #   255     - CTC TAT GAT ATA GAT GCC GAT ATT TAT AGT AA - #T AGA TTC AGG GGT ACA      993     Leu Tyr Asp Ile Asp Ala Asp Ile Tyr Ser As - #n Arg Phe Arg Gly Thr     260                 2 - #65                 2 - #70                 2 -     #75     - GTA AAG CCA ACC GAA AAA GAT TCT GAA GAA CA - #T CCC TTT ACC AGC GAG     1041     Val Lys Pro Thr Glu Lys Asp Ser Glu Glu Hi - #s Pro Phe Thr Ser Glu     #               290     - GGA ACA TTA GAA GGT GGT TTT TAT GGG CCT AA - #T GCT GAA GAA CTA GGG     1089     Gly Thr Leu Glu Gly Gly Phe Tyr Gly Pro As - #n Ala Glu Glu Leu Gly     #           305     - GGG AAA TTT TTA GCT ACG GAT AAC CGA GTT TT - #T GGG GTA TTT AGT GCC     1137     Gly Lys Phe Leu Ala Thr Asp Asn Arg Val Ph - #e Gly Val Phe Ser Ala     #       320     - AAA GAA ACG GAA GAA ACA AAA AAG GAA GCG TT - #A TCC AAG GAA ACC TTA     1185     Lys Glu Thr Glu Glu Thr Lys Lys Glu Ala Le - #u Ser Lys Glu Thr Leu     #   335     - ATT GAT GGC AAG CTA ATT ACT TTC TCT ACT AA - #A AAA ACC GAT GCA AAA     1233     Ile Asp Gly Lys Leu Ile Thr Phe Ser Thr Ly - #s Lys Thr Asp Ala Lys     340                 3 - #45                 3 - #50                 3 -     #55     - ACC AAT GCA ACA ACC AGT ACC GCA GCT AAT AC - #A ACA ACC GAT ACA ACC     1281     Thr Asn Ala Thr Thr Ser Thr Ala Ala Asn Th - #r Thr Thr Asp Thr Thr     #               370     - GCC AAT ACA ATA ACC GAT GAA AAA AAC TTT AA - #G ACG GAA GAT ATA TCA     1329     Ala Asn Thr Ile Thr Asp Glu Lys Asn Phe Ly - #s Thr Glu Asp Ile Ser     #           385     - AGT TTT GGT GAA GCT GAT TAT CTG TTA ATT GA - #C AAA TAT CCT ATT CCA     1377     Ser Phe Gly Glu Ala Asp Tyr Leu Leu Ile As - #p Lys Tyr Pro Ile Pro     #       400     - CTT TTA CCT GAT AAA AAT ACT AAT GAT TTC AT - #A AGT AGT AAG CAT CAT     1425     Leu Leu Pro Asp Lys Asn Thr Asn Asp Phe Il - #e Ser Ser Lys His His     #   415     - ACT GTA GGA AAT AAA CGC TAT AAA GTG GAA GC - #A TGT TGC AGT AAT CTA     1473     Thr Val Gly Asn Lys Arg Tyr Lys Val Glu Al - #a Cys Cys Ser Asn Leu     420                 4 - #25                 4 - #30                 4 -     #35     - AGC TAT GTG AAA TTT GGT ATG TAT TAT GAA GA - #C CCA CTT AAA GAA AAA     1521     Ser Tyr Val Lys Phe Gly Met Tyr Tyr Glu As - #p Pro Leu Lys Glu Lys     #               450     - GAA ACA GAA ACA GAA ACA GAA ACA GAA AAA GA - #C AAA GAA AAA GAA AAA     1569     Glu Thr Glu Thr Glu Thr Glu Thr Glu Lys As - #p Lys Glu Lys Glu Lys     #           465     - GAA AAA GAC AAA GAC AAA GAA AAA CAA ACG GC - #G GCA ACG ACC AAC ACT     1617     Glu Lys Asp Lys Asp Lys Glu Lys Gln Thr Al - #a Ala Thr Thr Asn Thr     #       480     - TAT TAT CAA TTC TTA TTA GGT CAC CGT ACT CC - #C AAG GAC GAC ATA CCT     1665     Tyr Tyr Gln Phe Leu Leu Gly His Arg Thr Pr - #o Lys Asp Asp Ile Pro     #   495     - AAA ACA GGA AGT GCA AAA TAT CAT GGT AGT TG - #G TTT GGT TAT ATT ACT     1713     Lys Thr Gly Ser Ala Lys Tyr His Gly Ser Tr - #p Phe Gly Tyr Ile Thr     500                 5 - #05                 5 - #10                 5 -     #15     - GAC GGT AAG ACA TCT TAC TCC CCC AGT GGT GA - #T AAG AAA CGC GAT AAA     1761     Asp Gly Lys Thr Ser Tyr Ser Pro Ser Gly As - #p Lys Lys Arg Asp Lys     #               530     - AAT GCT GTC GCC GAG TTT AAT GTT GAT TTT GC - #C GAG AAA AAG CTA ACA     1809     Asn Ala Val Ala Glu Phe Asn Val Asp Phe Al - #a Glu Lys Lys Leu Thr     #           545     - GGC GAA TTA AAA CGA CAC GAT ACT GGA AAT CC - #C GTA TTT AGT ATT GAG     1857     Gly Glu Leu Lys Arg His Asp Thr Gly Asn Pr - #o Val Phe Ser Ile Glu     #       560     - GCA AAC TTT AAT AAT AGT AGT AAT GCC TTC AC - #T GGT ACA GCA ACC GCA     1905     Ala Asn Phe Asn Asn Ser Ser Asn Ala Phe Th - #r Gly Thr Ala Thr Ala     #   575     - ACA AAT TTT GTA ATA GAT GGT AAA AAT AGT CA - #A AAT AAA AAT ACC CCA     1953     Thr Asn Phe Val Ile Asp Gly Lys Asn Ser Gl - #n Asn Lys Asn Thr Pro     580                 5 - #85                 5 - #90                 5 -     #95     - ATT AAT ATT ACA ACT AAA GTA AAC GGG GCA TT - #T TAT GGA CCT AAG GCT     2001     Ile Asn Ile Thr Thr Lys Val Asn Gly Ala Ph - #e Tyr Gly Pro Lys Ala     #               610     - TCT GAA TTA GGC GGT TAT TTC ACT TAT AAC GG - #A AAT TCT ACA GCT ACA     2049     Ser Glu Leu Gly Gly Tyr Phe Thr Tyr Asn Gl - #y Asn Ser Thr Ala Thr     #           625     - AAT TCT GAA AGT TCC TCA ACC GTA TCT TCA TC - #A TCC AAT TCA AAA AAT     2097     Asn Ser Glu Ser Ser Ser Thr Val Ser Ser Se - #r Ser Asn Ser Lys Asn     #       640     - GCA AGA GCT GCA GTT GTC TTT GGT GCG AGA CA - #A CAA GTA GAA ACA ACC     2145     Ala Arg Ala Ala Val Val Phe Gly Ala Arg Gl - #n Gln Val Glu Thr Thr     #   655     #TTT CGC CTA AGT       2194 ACT AAA AAA CCC TAT     # Met Thr Lys Lys Pro Tyr Phe Arg Leu Ser     #                 665 - #                 670     - ATT ATT TCT TGT CTT TTA ATT TCA TGC TAT GT - #A AAA GCA GAA ACT CAA     2242     Ile Ile Ser Cys Leu Leu Ile Ser Cys Tyr Va - #l Lys Ala Glu Thr Gln     #               685     - AGT ATA AAA GAT ACA AAA GAA GCT ATA TCA TC - #T GAA GTG GAC ACT CAA     2290     Ser Ile Lys Asp Thr Lys Glu Ala Ile Ser Se - #r Glu Val Asp Thr Gln     #           700     - AGT ACA GAA GAT TCA GAA TTA GAA ACT ATC TC - #A GTC ACT GCA GAA AAA     2338     Ser Thr Glu Asp Ser Glu Leu Glu Thr Ile Se - #r Val Thr Ala Glu Lys     #       715     - ATA AGA GAT CGT AAA GAT AAT GAA GTA ACT GG - #A CTT GGC AAA ATT ATC     2386     Ile Arg Asp Arg Lys Asp Asn Glu Val Thr Gl - #y Leu Gly Lys Ile Ile     #   730     - AAA ACT AGT GAA AGT ATC AGC CGA GAA CAA GT - #A TTA AAT ATT CGT GAT     2434     Lys Thr Ser Glu Ser Ile Ser Arg Glu Gln Va - #l Leu Asn Ile Arg Asp     735                 7 - #40                 7 - #45                 7 -     #50     - CTA ACA CGC TAT GAT CCA GGG ATT TCA GTT GT - #A GAA CAA GGT CGC GGT     2482     Leu Thr Arg Tyr Asp Pro Gly Ile Ser Val Va - #l Glu Gln Gly Arg Gly     #               765     - GCA AGT TCT GGA TAT TCT ATT CGT GGT ATG GA - #C AGA AAT AGA GTT GCT     2530     Ala Ser Ser Gly Tyr Ser Ile Arg Gly Met As - #p Arg Asn Arg Val Ala     #           780     - TTA TTA GTA GAT GGT TTA CCT CAA ACG CAA TC - #T TAT GTA GTG CAA AGC     2578     Leu Leu Val Asp Gly Leu Pro Gln Thr Gln Se - #r Tyr Val Val Gln Ser     #       795     - CCT TTA GTT GCT CGT TCA GGA TAT TCT GGC AC - #T GGT GCA ATT AAT GAA     2626     Pro Leu Val Ala Arg Ser Gly Tyr Ser Gly Th - #r Gly Ala Ile Asn Glu     #   810     - ATT GAA TAT GAA AAT GTA AAG GCC GTC GAA AT - #A AGC AAG GGG GGG AGT     2674     Ile Glu Tyr Glu Asn Val Lys Ala Val Glu Il - #e Ser Lys Gly Gly Ser     815                 8 - #20                 8 - #25                 8 -     #30     - TCT TCT GAG TAT GGT AAT GGA GCA CTA GCT GG - #T TCT GTA ACA TTT CAA     2722     Ser Ser Glu Tyr Gly Asn Gly Ala Leu Ala Gl - #y Ser Val Thr Phe Gln     #               845     - AGC AAA TCA GCA GCC GAT ATC TTA GAA GGA GA - #C AAA TCA TGG GGA ATT     2770     Ser Lys Ser Ala Ala Asp Ile Leu Glu Gly As - #p Lys Ser Trp Gly Ile     #           860     - CAA ACT AAA AAT GCT TAT TCA AGC AAA AAT AA - #A GGC TTT ACC CAT TCT     2818     Gln Thr Lys Asn Ala Tyr Ser Ser Lys Asn Ly - #s Gly Phe Thr His Ser     #       875     - TTA GCT GTA GCA GGA AAA CAA GGT GGA TTT GA - #A GGG CTA GCC ATT TAC     2866     Leu Ala Val Ala Gly Lys Gln Gly Gly Phe Gl - #u Gly Leu Ala Ile Tyr     #   890     - ACT CAA CGA AAT TCA ATT GAA ACC CAA GTC CA - #T AAA GAT GCA TTA AAA     2914     Thr Gln Arg Asn Ser Ile Glu Thr Gln Val Hi - #s Lys Asp Ala Leu Lys     895                 9 - #00                 9 - #05                 9 -     #10     - GGC GTA CAA AGT TAT GAT CGA TTA ATC GCC AC - #A ACA GAT AAA TCT TCA     2962     Gly Val Gln Ser Tyr Asp Arg Leu Ile Ala Th - #r Thr Asp Lys Ser Ser     #               925     - GGA TAC TTT GTG ATA CAA GGT GAG TGT CCA AA - #T GGT GAT GAC AAG TGT     3010     Gly Tyr Phe Val Ile Gln Gly Glu Cys Pro As - #n Gly Asp Asp Lys Cys     #           940     - GCA GCC AAG CCA CCT GCG ACT TTA TCC ACC CA - #A AGC GAA ACC GTA AGC     3058     Ala Ala Lys Pro Pro Ala Thr Leu Ser Thr Gl - #n Ser Glu Thr Val Ser     #       955     - GTT TCA GAT TAT ACG GGG GCT AAC CGT ATC AA - #A CCT AAT CCA ATG AAA     3106     Val Ser Asp Tyr Thr Gly Ala Asn Arg Ile Ly - #s Pro Asn Pro Met Lys     #   970     - TAT GAA AGC CAG TCT TGG TTT TTA AGA GGA GG - #G TAT CAT TTT TCT GAA     3154     Tyr Glu Ser Gln Ser Trp Phe Leu Arg Gly Gl - #y Tyr His Phe Ser Glu     975                 9 - #80                 9 - #85                 9 -     #90     - CAA CAT TAT ATT GGT GGT ATT TTT GAA TTC AC - #A CAA CAA AAA TTT GAT     3202     Gln His Tyr Ile Gly Gly Ile Phe Glu Phe Th - #r Gln Gln Lys Phe Asp     #              10050     - ATC CGT GAT ATG ACA TTT CCC GCT TAT TTA AG - #C CCA ACA GAA AGA CGG     3250     Ile Arg Asp Met Thr Phe Pro Ala Tyr Leu Se - #r Pro Thr Glu Arg Arg     #          10205     - GAT GAT AGT AGT CGT TCT TTT TAT CCA ATG CA - #A GAT CAT GGT GCA TAT     3298     Asp Asp Ser Ser Arg Ser Phe Tyr Pro Met Gl - #n Asp His Gly Ala Tyr     #      10350     - CAA CAT ATT GAG GAT GGC AGA GGC GTT AAA TA - #T GCA AGT GGG CTT TAT     3346     Gln His Ile Glu Asp Gly Arg Gly Val Lys Ty - #r Ala Ser Gly Leu Tyr     #  10505     - TTC GAT GAA CAC CAT AGA AAA CAG CGT GTA GG - #T ATT GAA TAT ATT TAC     3394     Phe Asp Glu His His Arg Lys Gln Arg Val Gl - #y Ile Glu Tyr Ile Tyr     #               10701060 - #                1065     - GAA AAT AAG AAC AAA GCG GGC ATC ATT GAC AA - #A GCA GTG TTA AGT GCT     3442     Glu Asn Lys Asn Lys Ala Gly Ile Ile Asp Ly - #s Ala Val Leu Ser Ala     #              10850     - AAT CAA CAA AAC ATC ATA CTT GAC AGT TAT AT - #G CGA CAT ACG CAT TGC     3490     Asn Gln Gln Asn Ile Ile Leu Asp Ser Tyr Me - #t Arg His Thr His Cys     #          11005     - AGT CTT TAT CCT AAT CCA AGT AAG AAT TGC CG - #C CCA ACA CTT GAT AAA     3538     Ser Leu Tyr Pro Asn Pro Ser Lys Asn Cys Ar - #g Pro Thr Leu Asp Lys     #      11150     - CCT TAT TCA TAC TAT CGT TCT GAT AGA AAT GT - #T TAT AAA GAA AAA CAT     3586     Pro Tyr Ser Tyr Tyr Arg Ser Asp Arg Asn Va - #l Tyr Lys Glu Lys His     #  11305     - AAT ATG TTG CAA TTG AAT TTA GAG AAA AAA AT - #T CAA CAA AAT TGG CTT     3634     Asn Met Leu Gln Leu Asn Leu Glu Lys Lys Il - #e Gln Gln Asn Trp Leu     #               11501140 - #                1145     - ACT CAT CAA ATT GTC TTC AAT CTT GGT TTT GA - #T GAC TTT ACT TCA GCG     3682     Thr His Gln Ile Val Phe Asn Leu Gly Phe As - #p Asp Phe Thr Ser Ala     #              11650     - CTT CAG CAT AAA GAT TAT TTA ACT CGA CGT GT - #T ATC GCT ACG GCA GAT     3730     Leu Gln His Lys Asp Tyr Leu Thr Arg Arg Va - #l Ile Ala Thr Ala Asp     #          11805     - AGT ATT CCA AGG AAA CCT GGT GAA ACT GGT AA - #A CCA AGA AAT GGT TTG     3778     Ser Ile Pro Arg Lys Pro Gly Glu Thr Gly Ly - #s Pro Arg Asn Gly Leu     #      11950     - CAA TCA CAA CCT TAC TTA TAC CCA AAA CCA GA - #G CCA TAT TTT GCA GGA     3826     Gln Ser Gln Pro Tyr Leu Tyr Pro Lys Pro Gl - #u Pro Tyr Phe Ala Gly     #  12105     - CAA GAT CAT TGT AAT TAT CAA GGT AGC TCC TC - #T AAT TAC AGA GAC TGT     3874     Gln Asp His Cys Asn Tyr Gln Gly Ser Ser Se - #r Asn Tyr Arg Asp Cys     #               12301220 - #                1225     - AAA GTG CGG TTA ATT AAA GGG AAA AAT TAT TA - #T TTC GCA GCA CGC AAT     3922     Lys Val Arg Leu Ile Lys Gly Lys Asn Tyr Ty - #r Phe Ala Ala Arg Asn     #              12450     - AAT ATG GCA TTA GGG AAA TAC GTT GAT TTA GG - #T TTA GGT ATT CGG TAT     3970     Asn Met Ala Leu Gly Lys Tyr Val Asp Leu Gl - #y Leu Gly Ile Arg Tyr     #          12605     - GAC GTA TCT CGT ACA AAA GCT AAT GAA TCA AC - #T ATT AGT GTT GGT AAA     4018     Asp Val Ser Arg Thr Lys Ala Asn Glu Ser Th - #r Ile Ser Val Gly Lys     #      12750     - TTT AAA AAT TTC TCT TGG AAT ACT GGT ATT GT - #C ATA AAA CCA ACG GAA     4066     Phe Lys Asn Phe Ser Trp Asn Thr Gly Ile Va - #l Ile Lys Pro Thr Glu     #  12905     - TGG CTT GAT CTT TCT TAT CGC CTT TCT ACT GG - #A TTT AGA AAT CCT AGT     4114     Trp Leu Asp Leu Ser Tyr Arg Leu Ser Thr Gl - #y Phe Arg Asn Pro Ser     #               13101300 - #                1305     - TTT TCT GAA ATG TAT GGT TGG CGG TAT GGT GG - #C AAG AAT GAC GAG GTT     4162     Phe Ser Glu Met Tyr Gly Trp Arg Tyr Gly Gl - #y Lys Asn Asp Glu Val     #              13250     - TAT GTA GGT AAA TTT AAG CCT GAA ACA TCT CG - #T AAC CAA GAG TTT GGT     4210     Tyr Val Gly Lys Phe Lys Pro Glu Thr Ser Ar - #g Asn Gln Glu Phe Gly     #          13405     - CTC GCT CTA AAA GGG GAT TTT GGT AAT ATT GA - #G ATC AGT CAT TTT AGT     4258     Leu Ala Leu Lys Gly Asp Phe Gly Asn Ile Gl - #u Ile Ser His Phe Ser     #      13550     - AAT GCT TAT CGA AAT CTT ATC GCC TTT GCT GA - #A GAA CTT AGT AAA AAT     4306     Asn Ala Tyr Arg Asn Leu Ile Ala Phe Ala Gl - #u Glu Leu Ser Lys Asn     #  13705     - GGA ACT GGA AAG GGC AAT TAT GGA TAT CAT AA - #T GCA CAA AAT GCA AAA     4354     Gly Thr Gly Lys Gly Asn Tyr Gly Tyr His As - #n Ala Gln Asn Ala Lys     #               13901380 - #                1385     - TTA GTT GGC GTA AAT ATA ACT GCA CAA TTA GA - #T TTT AAT GGT TTA TGG     4402     Leu Val Gly Val Asn Ile Thr Ala Gln Leu As - #p Phe Asn Gly Leu Trp     #              14050     - AAA CGT ATT CCC TAC GGT TGG TAT GCA ACA TT - #T GCT TAT AAC CAA GTA     4450     Lys Arg Ile Pro Tyr Gly Trp Tyr Ala Thr Ph - #e Ala Tyr Asn Gln Val     #          14205     - AAA GTT AAA GAT CAA AAA ATC AAT GCT GGT TT - #A GCC TCC GTA AGC AGT     4498     Lys Val Lys Asp Gln Lys Ile Asn Ala Gly Le - #u Ala Ser Val Ser Ser     #      14350     - TAT TTA TTT GAT GCC ATT CAG CCC AGC CGT TA - #T ATC ATT GGT TTA GGC     4546     Tyr Leu Phe Asp Ala Ile Gln Pro Ser Arg Ty - #r Ile Ile Gly Leu Gly     #  14505     - TAT GAT CAT CCA AGT AAT ACT TGG GGA ATT AA - #T ACA ATG TTT ACT CAA     4594     Tyr Asp His Pro Ser Asn Thr Trp Gly Ile As - #n Thr Met Phe Thr Gln     #               14701460 - #                1465     - TCA AAA GCA AAA TCT CAA AAT GAA TTG CTA GG - #A AAA CGT GCA TTA GGT     4642     Ser Lys Ala Lys Ser Gln Asn Glu Leu Leu Gl - #y Lys Arg Ala Leu Gly     #              14850     - AAC AAT TCA AGG GAT GTA AAA TCA ACA AGA AA - #A CTT ACT CGG GCA TGG     4690     Asn Asn Ser Arg Asp Val Lys Ser Thr Arg Ly - #s Leu Thr Arg Ala Trp     #          15005     - CAT ATC TTA GAT GTA TCG GGT TAT TAC ATG GC - #G AAT AAA AAT ATT ATG     4738     His Ile Leu Asp Val Ser Gly Tyr Tyr Met Al - #a Asn Lys Asn Ile Met     #      15150     - CTT CGA TTA GGG ATA TAT AAT TTA TTC AAC TA - #T CGC TAT GTT ACT TGG     4786     Leu Arg Leu Gly Ile Tyr Asn Leu Phe Asn Ty - #r Arg Tyr Val Thr Trp     #  15305     - GAA GCG GTG CGT CAA ACA GCA CAA GGT GCG GT - #C AAT CAA CAT CAA AAT     4834     Glu Ala Val Arg Gln Thr Ala Gln Gly Ala Va - #l Asn Gln His Gln Asn     #               15501540 - #                1545     - GTT GGT AGC TAT ACT CGC TAC GCA GCA TCA GG - #A CGA AAC TAT ACC TTA     4882     Val Gly Ser Tyr Thr Arg Tyr Ala Ala Ser Gl - #y Arg Asn Tyr Thr Leu     #              15650     - ACA TTA GAA ATG AAA TTC TAAATTAAAA TGCGCCAGAT GG - #ACTAGATA     4930     Thr Leu Glu Met Lys Phe                 1570     - TGCTATATCT ATACCTTACT GGCGCATCTT TTTCTGTTCT ATAATCTGCT TA - #AGTGAAAA     4990     #                 503 - #3GATCTTTT CACACATTTA TTG     - (2) INFORMATION FOR SEQ ID NO:3:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 5009 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: double               (D) TOPOLOGY: linear     -     (ix) FEATURE:               (A) NAME/KEY: CDS               (B) LOCATION: join(121..21 - #00, 2117..4852)     #ID NO:3: (xi) SEQUENCE DESCRIPTION: SEQ     - ATTTGTTTTA CGCCATTTTT CATATTTTAT CCATGAACTT AAAAAACTCT AA - #CTTGACAT       60     - TATTACAAAA AAAGATCAAT AATGCGAATT ATTATCAATT TTGTATGAGT AT - #ATAATTCT      120     - ATG AAA TCT GTA CCT CTT ATC TCT GGT GGA CT - #T TCC TTT TTA CTA AGT      168     Met Lys Ser Val Pro Leu Ile Ser Gly Gly Le - #u Ser Phe Leu Leu Ser     #                 15     - GCT TGT AGC GGA GGG GGG TCT TTT GAT GTA GA - #T AAC GTC TCT AAT ACC      216     Ala Cys Ser Gly Gly Gly Ser Phe Asp Val As - #p Asn Val Ser Asn Thr     #             30     - CCC TCT TCT AAA CCA CGT TAT CAA GAC GAT AC - #C TCG AAT CAA AGA AAA      264     Pro Ser Ser Lys Pro Arg Tyr Gln Asp Asp Th - #r Ser Asn Gln Arg Lys     #         45     - AAA TCT AAT TTG AAA AAG TTG TTC ATT CCT TC - #T TTA GGA GGA GGG ATG      312     Lys Ser Asn Leu Lys Lys Leu Phe Ile Pro Se - #r Leu Gly Gly Gly Met     #     60     - AAA TTG GTG GCT CAG AAT CTT CGT GGT AAT AA - #A GAA CCT AGT TTC TTA      360     Lys Leu Val Ala Gln Asn Leu Arg Gly Asn Ly - #s Glu Pro Ser Phe Leu     # 80     - AAT GAA GAT GAC TAT ATA TCA TAT TTT TCC TC - #A CTT TCT ACG ATT GAA      408     Asn Glu Asp Asp Tyr Ile Ser Tyr Phe Ser Se - #r Leu Ser Thr Ile Glu     #                 95     - AAG GAT GTT AAA GAT AAC AAT AAA AAC GGG GC - #G GAC CTT ATT GGC TCA      456     Lys Asp Val Lys Asp Asn Asn Lys Asn Gly Al - #a Asp Leu Ile Gly Ser     #           110     - ATA GAC GAG CCT AGT ACA ACA AAT CCA CCC GA - #A AAG CAT CAT GGA CAA      504     Ile Asp Glu Pro Ser Thr Thr Asn Pro Pro Gl - #u Lys His His Gly Gln     #       125     - AAA TAT GTA TAT TCA GGG CTT TAT TAT ACT CC - #A TCG TGG AGT TTA AAC      552     Lys Tyr Val Tyr Ser Gly Leu Tyr Tyr Thr Pr - #o Ser Trp Ser Leu Asn     #   140     - GAT TCT AAA AAC AAG TTT TAT TTA GGT TAC TA - #T GGA TAT GCG TTT TAT      600     Asp Ser Lys Asn Lys Phe Tyr Leu Gly Tyr Ty - #r Gly Tyr Ala Phe Tyr     145                 1 - #50                 1 - #55                 1 -     #60     - TAT GGT AAT AAA ACT GCA ACA AAC TTG CCA GT - #A AAC GGT GTA GCT AAA      648     Tyr Gly Asn Lys Thr Ala Thr Asn Leu Pro Va - #l Asn Gly Val Ala Lys     #               175     - TAC AAA GGA ACT TGG GAT TTC ATC ACT GCA AC - #T AAA AAT GGC AAA CGT      696     Tyr Lys Gly Thr Trp Asp Phe Ile Thr Ala Th - #r Lys Asn Gly Lys Arg     #           190     - TAT CCT TTG TTA AGT AAT GGC AGT CAC GCT TA - #T TAT CGA CGT AGT GCA      744     Tyr Pro Leu Leu Ser Asn Gly Ser His Ala Ty - #r Tyr Arg Arg Ser Ala     #       205     - ATT CCA GAA GAT ATT GAT TTA GAA AAT GAT TC - #A AAG AAT GGT GAT ATA      792     Ile Pro Glu Asp Ile Asp Leu Glu Asn Asp Se - #r Lys Asn Gly Asp Ile     #   220     - GGC TTA ATA AGT GAA TTT AGT GCA GAT TTT GG - #G ACT AAA AAA CTG ACA      840     Gly Leu Ile Ser Glu Phe Ser Ala Asp Phe Gl - #y Thr Lys Lys Leu Thr     225                 2 - #30                 2 - #35                 2 -     #40     - GGA CAA CTG TCT TAC ACC AAA AGA AAA ACT AA - #T AAT CAA CCA TAT GAA      888     Gly Gln Leu Ser Tyr Thr Lys Arg Lys Thr As - #n Asn Gln Pro Tyr Glu     #               255     - AAG AAA AAA CTC TAT GAT ATA GAT GCC GAT AT - #T TAT AGT AAT AGA TTC      936     Lys Lys Lys Leu Tyr Asp Ile Asp Ala Asp Il - #e Tyr Ser Asn Arg Phe     #           270     - AGG GGT ACA GTA AAG CCA ACC GAA AAA GAT TC - #T GAA GAA CAT CCC TTT      984     Arg Gly Thr Val Lys Pro Thr Glu Lys Asp Se - #r Glu Glu His Pro Phe     #       285     - ACC AGC GAG GGA ACA TTA GAA GGT GGT TTT TA - #T GGG CCT AAT GCT GAA     1032     Thr Ser Glu Gly Thr Leu Glu Gly Gly Phe Ty - #r Gly Pro Asn Ala Glu     #   300     - GAA CTA GGG GGG AAA TTT TTA GCT ACG GAT AA - #C CGA GTT TTT GGG GTA     1080     Glu Leu Gly Gly Lys Phe Leu Ala Thr Asp As - #n Arg Val Phe Gly Val     305                 3 - #10                 3 - #15                 3 -     #20     - TTT AGT GCC AAA GAA ACG GAA GAA ACA AAA AA - #G GAA GCG TTA TCC AAG     1128     Phe Ser Ala Lys Glu Thr Glu Glu Thr Lys Ly - #s Glu Ala Leu Ser Lys     #               335     - GAA ACC TTA ATT GAT GGC AAG CTA ATT ACT TT - #C TCT ACT AAA AAA ACC     1176     Glu Thr Leu Ile Asp Gly Lys Leu Ile Thr Ph - #e Ser Thr Lys Lys Thr     #           350     - GAT GCA AAA ACC AAT GCA ACA ACC AGT ACC GC - #A GCT AAT ACA ACA ACC     1224     Asp Ala Lys Thr Asn Ala Thr Thr Ser Thr Al - #a Ala Asn Thr Thr Thr     #       365     - GAT ACA ACC GCC AAT ACA ATA ACC GAT GAA AA - #A AAC TTT AAG ACG GAA     1272     Asp Thr Thr Ala Asn Thr Ile Thr Asp Glu Ly - #s Asn Phe Lys Thr Glu     #   380     - GAT ATA TCA AGT TTT GGT GAA GCT GAT TAT CT - #G TTA ATT GAC AAA TAT     1320     Asp Ile Ser Ser Phe Gly Glu Ala Asp Tyr Le - #u Leu Ile Asp Lys Tyr     385                 3 - #90                 3 - #95                 4 -     #00     - CCT ATT CCA CTT TTA CCT GAT AAA AAT ACT AA - #T GAT TTC ATA AGT AGT     1368     Pro Ile Pro Leu Leu Pro Asp Lys Asn Thr As - #n Asp Phe Ile Ser Ser     #               415     - AAG CAT CAT ACT GTA GGA AAT AAA CGC TAT AA - #A GTG GAA GCA TGT TGC     1416     Lys His His Thr Val Gly Asn Lys Arg Tyr Ly - #s Val Glu Ala Cys Cys     #           430     - AGT AAT CTA AGC TAT GTG AAA TTT GGT ATG TA - #T TAT GAA GAC CCA CTT     1464     Ser Asn Leu Ser Tyr Val Lys Phe Gly Met Ty - #r Tyr Glu Asp Pro Leu     #       445     - AAA GAA AAA GAA ACA GAA ACA GAA ACA GAA AC - #A GAA AAA GAC AAA GAA     1512     Lys Glu Lys Glu Thr Glu Thr Glu Thr Glu Th - #r Glu Lys Asp Lys Glu     #   460     - AAA GAA AAA GAA AAA GAC AAA GAC AAA GAA AA - #A CAA ACG GCG GCA ACG     1560     Lys Glu Lys Glu Lys Asp Lys Asp Lys Glu Ly - #s Gln Thr Ala Ala Thr     465                 4 - #70                 4 - #75                 4 -     #80     - ACC AAC ACT TAT TAT CAA TTC TTA TTA GGT CA - #C CGT ACT CCC AAG GAC     1608     Thr Asn Thr Tyr Tyr Gln Phe Leu Leu Gly Hi - #s Arg Thr Pro Lys Asp     #               495     - GAC ATA CCT AAA ACA GGA AGT GCA AAA TAT CA - #T GGT AGT TGG TTT GGT     1656     Asp Ile Pro Lys Thr Gly Ser Ala Lys Tyr Hi - #s Gly Ser Trp Phe Gly     #           510     - TAT ATT ACT GAC GGT AAG ACA TCT TAC TCC CC - #C AGT GGT GAT AAG AAA     1704     Tyr Ile Thr Asp Gly Lys Thr Ser Tyr Ser Pr - #o Ser Gly Asp Lys Lys     #       525     - CGC GAT AAA AAT GCT GTC GCC GAG TTT AAT GT - #T GAT TTT GCC GAG AAA     1752     Arg Asp Lys Asn Ala Val Ala Glu Phe Asn Va - #l Asp Phe Ala Glu Lys     #   540     - AAG CTA ACA GGC GAA TTA AAA CGA CAC GAT AC - #T GGA AAT CCC GTA TTT     1800     Lys Leu Thr Gly Glu Leu Lys Arg His Asp Th - #r Gly Asn Pro Val Phe     545                 5 - #50                 5 - #55                 5 -     #60     - AGT ATT GAG GCA AAC TTT AAT AAT AGT AGT AA - #T GCC TTC ACT GGT ACA     1848     Ser Ile Glu Ala Asn Phe Asn Asn Ser Ser As - #n Ala Phe Thr Gly Thr     #               575     - GCA ACC GCA ACA AAT TTT GTA ATA GAT GGT AA - #A AAT AGT CAA AAT AAA     1896     Ala Thr Ala Thr Asn Phe Val Ile Asp Gly Ly - #s Asn Ser Gln Asn Lys     #           590     - AAT ACC CCA ATT AAT ATT ACA ACT AAA GTA AA - #C GGG GCA TTT TAT GGA     1944     Asn Thr Pro Ile Asn Ile Thr Thr Lys Val As - #n Gly Ala Phe Tyr Gly     #       605     - CCT AAG GCT TCT GAA TTA GGC GGT TAT TTC AC - #T TAT AAC GGA AAT TCT     1992     Pro Lys Ala Ser Glu Leu Gly Gly Tyr Phe Th - #r Tyr Asn Gly Asn Ser     #   620     - ACA GCT ACA AAT TCT GAA AGT TCC TCA ACC GT - #A TCT TCA TCA TCC AAT     2040     Thr Ala Thr Asn Ser Glu Ser Ser Ser Thr Va - #l Ser Ser Ser Ser Asn     625                 6 - #30                 6 - #35                 6 -     #40     - TCA AAA AAT GCA AGA GCT GCA GTT GTC TTT GG - #T GCG AGA CAA CAA GTA     2088     Ser Lys Asn Ala Arg Ala Ala Val Val Phe Gl - #y Ala Arg Gln Gln Val     #               655     #AAA CCC TAT TTT       2137A CTAAAA ATG ACT AAA     #       Met Thr Lys Lys Pro Tyr P - #he     #           665     - CGC CTA AGT ATT ATT TCT TGT CTT TTA ATT TC - #A TGC TAT GTA AAA GCA     2185     Arg Leu Ser Ile Ile Ser Cys Leu Leu Ile Se - #r Cys Tyr Val Lys Ala     #       680     - GAA ACT CAA AGT ATA AAA GAT ACA AAA GAA GC - #T ATA TCA TCT GAA GTG     2233     Glu Thr Gln Ser Ile Lys Asp Thr Lys Glu Al - #a Ile Ser Ser Glu Val     #   695     - GAC ACT CAA AGT ACA GAA GAT TCA GAA TTA GA - #A ACT ATC TCA GTC ACT     2281     Asp Thr Gln Ser Thr Glu Asp Ser Glu Leu Gl - #u Thr Ile Ser Val Thr     700                 7 - #05                 7 - #10                 7 -     #15     - GCA GAA AAA ATA AGA GAT CGT AAA GAT AAT GA - #A GTA ACT GGA CTT GGC     2329     Ala Glu Lys Ile Arg Asp Arg Lys Asp Asn Gl - #u Val Thr Gly Leu Gly     #               730     - AAA ATT ATC AAA ACT AGT GAA AGT ATC AGC CG - #A GAA CAA GTA TTA AAT     2377     Lys Ile Ile Lys Thr Ser Glu Ser Ile Ser Ar - #g Glu Gln Val Leu Asn     #           745     - ATT CGT GAT CTA ACA CGC TAT GAT CCA GGG AT - #T TCA GTT GTA GAA CAA     2425     Ile Arg Asp Leu Thr Arg Tyr Asp Pro Gly Il - #e Ser Val Val Glu Gln     #       760     - GGT CGC GGT GCA AGT TCT GGA TAT TCT ATT CG - #T GGT ATG GAC AGA AAT     2473     Gly Arg Gly Ala Ser Ser Gly Tyr Ser Ile Ar - #g Gly Met Asp Arg Asn     #   775     - AGA GTT GCT TTA TTA GTA GAT GGT TTA CCT CA - #A ACG CAA TCT TAT GTA     2521     Arg Val Ala Leu Leu Val Asp Gly Leu Pro Gl - #n Thr Gln Ser Tyr Val     780                 7 - #85                 7 - #90                 7 -     #95     - GTG CAA AGC CCT TTA GTT GCT CGT TCA GGA TA - #T TCT GGC ACT GGT GCA     2569     Val Gln Ser Pro Leu Val Ala Arg Ser Gly Ty - #r Ser Gly Thr Gly Ala     #               810     - ATT AAT GAA ATT GAA TAT GAA AAT GTA AAG GC - #C GTC GAA ATA AGC AAG     2617     Ile Asn Glu Ile Glu Tyr Glu Asn Val Lys Al - #a Val Glu Ile Ser Lys     #           825     - GGG GGG AGT TCT TCT GAG TAT GGT AAT GGA GC - #A CTA GCT GGT TCT GTA     2665     Gly Gly Ser Ser Ser Glu Tyr Gly Asn Gly Al - #a Leu Ala Gly Ser Val     #       840     - ACA TTT CAA AGC AAA TCA GCA GCC GAT ATC TT - #A GAA GGA GAC AAA TCA     2713     Thr Phe Gln Ser Lys Ser Ala Ala Asp Ile Le - #u Glu Gly Asp Lys Ser     #   855     - TGG GGA ATT CAA ACT AAA AAT GCT TAT TCA AG - #C AAA AAT AAA GGC TTT     2761     Trp Gly Ile Gln Thr Lys Asn Ala Tyr Ser Se - #r Lys Asn Lys Gly Phe     860                 8 - #65                 8 - #70                 8 -     #75     - ACC CAT TCT TTA GCT GTA GCA GGA AAA CAA GG - #T GGA TTT GAA GGG CTA     2809     Thr His Ser Leu Ala Val Ala Gly Lys Gln Gl - #y Gly Phe Glu Gly Leu     #               890     - GCC ATT TAC ACT CAA CGA AAT TCA ATT GAA AC - #C CAA GTC CAT AAA GAT     2857     Ala Ile Tyr Thr Gln Arg Asn Ser Ile Glu Th - #r Gln Val His Lys Asp     #           905     - GCA TTA AAA GGC GTA CAA AGT TAT GAT CGA TT - #A ATC GCC ACA ACA GAT     2905     Ala Leu Lys Gly Val Gln Ser Tyr Asp Arg Le - #u Ile Ala Thr Thr Asp     #       920     - AAA TCT TCA GGA TAC TTT GTG ATA CAA GGT GA - #G TGT CCA AAT GGT GAT     2953     Lys Ser Ser Gly Tyr Phe Val Ile Gln Gly Gl - #u Cys Pro Asn Gly Asp     #   935     - GAC AAG TGT GCA GCC AAG CCA CCT GCG ACT TT - #A TCC ACC CAA AGC GAA     3001     Asp Lys Cys Ala Ala Lys Pro Pro Ala Thr Le - #u Ser Thr Gln Ser Glu     940                 9 - #45                 9 - #50                 9 -     #55     - ACC GTA AGC GTT TCA GAT TAT ACG GGG GCT AA - #C CGT ATC AAA CCT AAT     3049     Thr Val Ser Val Ser Asp Tyr Thr Gly Ala As - #n Arg Ile Lys Pro Asn     #               970     - CCA ATG AAA TAT GAA AGC CAG TCT TGG TTT TT - #A AGA GGA GGG TAT CAT     3097     Pro Met Lys Tyr Glu Ser Gln Ser Trp Phe Le - #u Arg Gly Gly Tyr His     #           985     - TTT TCT GAA CAA CAT TAT ATT GGT GGT ATT TT - #T GAA TTC ACA CAA CAA     3145     Phe Ser Glu Gln His Tyr Ile Gly Gly Ile Ph - #e Glu Phe Thr Gln Gln     #       1000     - AAA TTT GAT ATC CGT GAT ATG ACA TTT CCC GC - #T TAT TTA AGC CCA ACA     3193     Lys Phe Asp Ile Arg Asp Met Thr Phe Pro Al - #a Tyr Leu Ser Pro Thr     #  10150     - GAA AGA CGG GAT GAT AGT AGT CGT TCT TTT TA - #T CCA ATG CAA GAT CAT     3241     Glu Arg Arg Asp Asp Ser Ser Arg Ser Phe Ty - #r Pro Met Gln Asp His     #               10351025 - #                1030     - GGT GCA TAT CAA CAT ATT GAG GAT GGC AGA GG - #C GTT AAA TAT GCA AGT     3289     Gly Ala Tyr Gln His Ile Glu Asp Gly Arg Gl - #y Val Lys Tyr Ala Ser     #              10505     - GGG CTT TAT TTC GAT GAA CAC CAT AGA AAA CA - #G CGT GTA GGT ATT GAA     3337     Gly Leu Tyr Phe Asp Glu His His Arg Lys Gl - #n Arg Val Gly Ile Glu     #          10650     - TAT ATT TAC GAA AAT AAG AAC AAA GCG GGC AT - #C ATT GAC AAA GCA GTG     3385     Tyr Ile Tyr Glu Asn Lys Asn Lys Ala Gly Il - #e Ile Asp Lys Ala Val     #      10805     - TTA AGT GCT AAT CAA CAA AAC ATC ATA CTT GA - #C AGT TAT ATG CGA CAT     3433     Leu Ser Ala Asn Gln Gln Asn Ile Ile Leu As - #p Ser Tyr Met Arg His     #  10950     - ACG CAT TGC AGT CTT TAT CCT AAT CCA AGT AA - #G AAT TGC CGC CCA ACA     3481     Thr His Cys Ser Leu Tyr Pro Asn Pro Ser Ly - #s Asn Cys Arg Pro Thr     #               11151105 - #                1110     - CTT GAT AAA CCT TAT TCA TAC TAT CGT TCT GA - #T AGA AAT GTT TAT AAA     3529     Leu Asp Lys Pro Tyr Ser Tyr Tyr Arg Ser As - #p Arg Asn Val Tyr Lys     #              11305     - GAA AAA CAT AAT ATG TTG CAA TTG AAT TTA GA - #G AAA AAA ATT CAA CAA     3577     Glu Lys His Asn Met Leu Gln Leu Asn Leu Gl - #u Lys Lys Ile Gln Gln     #          11450     - AAT TGG CTT ACT CAT CAA ATT GTC TTC AAT CT - #T GGT TTT GAT GAC TTT     3625     Asn Trp Leu Thr His Gln Ile Val Phe Asn Le - #u Gly Phe Asp Asp Phe     #      11605     - ACT TCA GCG CTT CAG CAT AAA GAT TAT TTA AC - #T CGA CGT GTT ATC GCT     3673     Thr Ser Ala Leu Gln His Lys Asp Tyr Leu Th - #r Arg Arg Val Ile Ala     #  11750     - ACG GCA GAT AGT ATT CCA AGG AAA CCT GGT GA - #A ACT GGT AAA CCA AGA     3721     Thr Ala Asp Ser Ile Pro Arg Lys Pro Gly Gl - #u Thr Gly Lys Pro Arg     #               11951185 - #                1190     - AAT GGT TTG CAA TCA CAA CCT TAC TTA TAC CC - #A AAA CCA GAG CCA TAT     3769     Asn Gly Leu Gln Ser Gln Pro Tyr Leu Tyr Pr - #o Lys Pro Glu Pro Tyr     #              12105     - TTT GCA GGA CAA GAT CAT TGT AAT TAT CAA GG - #T AGC TCC TCT AAT TAC     3817     Phe Ala Gly Gln Asp His Cys Asn Tyr Gln Gl - #y Ser Ser Ser Asn Tyr     #          12250     - AGA GAC TGT AAA GTG CGG TTA ATT AAA GGG AA - #A AAT TAT TAT TTC GCA     3865     Arg Asp Cys Lys Val Arg Leu Ile Lys Gly Ly - #s Asn Tyr Tyr Phe Ala     #      12405     - GCA CGC AAT AAT ATG GCA TTA GGG AAA TAC GT - #T GAT TTA GGT TTA GGT     3913     Ala Arg Asn Asn Met Ala Leu Gly Lys Tyr Va - #l Asp Leu Gly Leu Gly     #  12550     - ATT CGG TAT GAC GTA TCT CGT ACA AAA GCT AA - #T GAA TCA ACT ATT AGT     3961     Ile Arg Tyr Asp Val Ser Arg Thr Lys Ala As - #n Glu Ser Thr Ile Ser     #               12751265 - #                1270     - GTT GGT AAA TTT AAA AAT TTC TCT TGG AAT AC - #T GGT ATT GTC ATA AAA     4009     Val Gly Lys Phe Lys Asn Phe Ser Trp Asn Th - #r Gly Ile Val Ile Lys     #              12905     - CCA ACG GAA TGG CTT GAT CTT TCT TAT CGC CT - #T TCT ACT GGA TTT AGA     4057     Pro Thr Glu Trp Leu Asp Leu Ser Tyr Arg Le - #u Ser Thr Gly Phe Arg     #          13050     - AAT CCT AGT TTT TCT GAA ATG TAT GGT TGG CG - #G TAT GGT GGC AAG AAT     4105     Asn Pro Ser Phe Ser Glu Met Tyr Gly Trp Ar - #g Tyr Gly Gly Lys Asn     #      13205     - GAC GAG GTT TAT GTA GGT AAA TTT AAG CCT GA - #A ACA TCT CGT AAC CAA     4153     Asp Glu Val Tyr Val Gly Lys Phe Lys Pro Gl - #u Thr Ser Arg Asn Gln     #  13350     - GAG TTT GGT CTC GCT CTA AAA GGG GAT TTT GG - #T AAT ATT GAG ATC AGT     4201     Glu Phe Gly Leu Ala Leu Lys Gly Asp Phe Gl - #y Asn Ile Glu Ile Ser     #               13551345 - #                1350     - CAT TTT AGT AAT GCT TAT CGA AAT CTT ATC GC - #C TTT GCT GAA GAA CTT     4249     His Phe Ser Asn Ala Tyr Arg Asn Leu Ile Al - #a Phe Ala Glu Glu Leu     #              13705     - AGT AAA AAT GGA ACT GGA AAG GGC AAT TAT GG - #A TAT CAT AAT GCA CAA     4297     Ser Lys Asn Gly Thr Gly Lys Gly Asn Tyr Gl - #y Tyr His Asn Ala Gln     #          13850     - AAT GCA AAA TTA GTT GGC GTA AAT ATA ACT GC - #A CAA TTA GAT TTT AAT     4345     Asn Ala Lys Leu Val Gly Val Asn Ile Thr Al - #a Gln Leu Asp Phe Asn     #      14005     - GGT TTA TGG AAA CGT ATT CCC TAC GGT TGG TA - #T GCA ACA TTT GCT TAT     4393     Gly Leu Trp Lys Arg Ile Pro Tyr Gly Trp Ty - #r Ala Thr Phe Ala Tyr     #  14150     - AAC CAA GTA AAA GTT AAA GAT CAA AAA ATC AA - #T GCT GGT TTA GCC TCC     4441     Asn Gln Val Lys Val Lys Asp Gln Lys Ile As - #n Ala Gly Leu Ala Ser     #               14351425 - #                1430     - GTA AGC AGT TAT TTA TTT GAT GCC ATT CAG CC - #C AGC CGT TAT ATC ATT     4489     Val Ser Ser Tyr Leu Phe Asp Ala Ile Gln Pr - #o Ser Arg Tyr Ile Ile     #              14505     - GGT TTA GGC TAT GAT CAT CCA AGT AAT ACT TG - #G GGA ATT AAT ACA ATG     4537     Gly Leu Gly Tyr Asp His Pro Ser Asn Thr Tr - #p Gly Ile Asn Thr Met     #          14650     - TTT ACT CAA TCA AAA GCA AAA TCT CAA AAT GA - #A TTG CTA GGA AAA CGT     4585     Phe Thr Gln Ser Lys Ala Lys Ser Gln Asn Gl - #u Leu Leu Gly Lys Arg     #      14805     - GCA TTA GGT AAC AAT TCA AGG GAT GTA AAA TC - #A ACA AGA AAA CTT ACT     4633     Ala Leu Gly Asn Asn Ser Arg Asp Val Lys Se - #r Thr Arg Lys Leu Thr     #  14950     - CGG GCA TGG CAT ATC TTA GAT GTA TCG GGT TA - #T TAC ATG GCG AAT AAA     4681     Arg Ala Trp His Ile Leu Asp Val Ser Gly Ty - #r Tyr Met Ala Asn Lys     #               15151505 - #                1510     - AAT ATT ATG CTT CGA TTA GGG ATA TAT AAT TT - #A TTC AAC TAT CGC TAT     4729     Asn Ile Met Leu Arg Leu Gly Ile Tyr Asn Le - #u Phe Asn Tyr Arg Tyr     #              15305     - GTT ACT TGG GAA GCG GTG CGT CAA ACA GCA CA - #A GGT GCG GTC AAT CAA     4777     Val Thr Trp Glu Ala Val Arg Gln Thr Ala Gl - #n Gly Ala Val Asn Gln     #          15450     - CAT CAA AAT GTT GGT AGC TAT ACT CGC TAC GC - #A GCA TCA GGA CGA AAC     4825     His Gln Asn Val Gly Ser Tyr Thr Arg Tyr Al - #a Ala Ser Gly Arg Asn     #      15605     - TAT ACC TTA ACA TTA GAA ATG AAA TTC TAAATTAAA - #A TGCGCCAGAT     4872     Tyr Thr Leu Thr Leu Glu Met Lys Phe     #   1570     - GGACTAGATA TGCTATATCT ATACCTTACT GGCGCATCTT TTTCTGTTCT AT - #AATCTGCT     4932     - TAAGTGAAAA ACCAAACTTG GATTTTTTAC AAGATCTTTT CACACATTTA TT - #GTAAAATC     4992     # 5009             G     - (2) INFORMATION FOR SEQ ID NO:4:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 5099 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: double               (D) TOPOLOGY: linear     -     (ix) FEATURE:               (A) NAME/KEY: CDS               (B) LOCATION: join(160..21 - #21, 2152..4890)     #ID NO:4: (xi) SEQUENCE DESCRIPTION: SEQ     - AAAATTCGGT AATGATAACC CTATAAATGA TAAGAGAGAA AGTTGTTTTA CG - #CCATTTTT       60     - CATATTTTAT CCATGAACTT AAAAAATTCT AAGTTGACAT TATTACAAAA AA - #AGAACAAT      120     - AATGCGAATT ATTATCAATT TTGTATAAGT ATTAATTCT ATG AAA TCT - # GTA CCT      174     #       Met Lys Ser Val Pro     #      5  1     - CTT ATC ACT GGT GGA CTT TCC TTT TTA CTA AG - #C GCT TGT AGC GGG GGA      222     Leu Ile Thr Gly Gly Leu Ser Phe Leu Leu Se - #r Ala Cys Ser Gly Gly     #                 20     - GGT GGT TCT TTT GAT GTA GAT GAC GTC TCT AA - #T CCC TCC TCT TCT AAA      270     Gly Gly Ser Phe Asp Val Asp Asp Val Ser As - #n Pro Ser Ser Ser Lys     #             35     - CCA CGT TAT CAA GAC GAT ACC TCG AAT CAA AG - #A ACA AAA TCT GAT TTG      318     Pro Arg Tyr Gln Asp Asp Thr Ser Asn Gln Ar - #g Thr Lys Ser Asp Leu     #         50     - GAA AAG TTG TTC ATT CCT TCT TTA GGG GGA GG - #G ATG AAG TTA GTG GCT      366     Glu Lys Leu Phe Ile Pro Ser Leu Gly Gly Gl - #y Met Lys Leu Val Ala     #     65     - CAA AAT TTT ATT GGT GCT AGA GAA CCT AGT TT - #C TTA AAT GAA GAT GGC      414     Gln Asn Phe Ile Gly Ala Arg Glu Pro Ser Ph - #e Leu Asn Glu Asp Gly     # 85     - TAT ATG ATA TTT TCC TCA CTT TCT ACG ATT GA - #A GAG GAT GTT GAA AAA      462     Tyr Met Ile Phe Ser Ser Leu Ser Thr Ile Gl - #u Glu Asp Val Glu Lys     #                100     - GTT AAA AAT AAC AAT AAA AAC GGG GGG AGG CT - #T ATT GGC TCA ATT GAG      510     Val Lys Asn Asn Asn Lys Asn Gly Gly Arg Le - #u Ile Gly Ser Ile Glu     #           115     - GAA CCT AAT GGA ACA TCA CAA AAT TCT AAT TC - #A CAA GAA TAC GTT TAT      558     Glu Pro Asn Gly Thr Ser Gln Asn Ser Asn Se - #r Gln Glu Tyr Val Tyr     #       130     - TCT GGT TTG TAT TAT ATC GAT AGT TGG CGT GA - #T TAT AAG AAG GAA GAG      606     Ser Gly Leu Tyr Tyr Ile Asp Ser Trp Arg As - #p Tyr Lys Lys Glu Glu     #   145     - CAA AAA GCT TAT ACT GGC TAT TAT GGT TAT GC - #A TTT TAT TAT GGT AAT      654     Gln Lys Ala Tyr Thr Gly Tyr Tyr Gly Tyr Al - #a Phe Tyr Tyr Gly Asn     150                 1 - #55                 1 - #60                 1 -     #65     - GAA ACT GCA AAA AAC TTG CCA GTA AAA GGT GT - #A GCT AAA TAC AAA GGA      702     Glu Thr Ala Lys Asn Leu Pro Val Lys Gly Va - #l Ala Lys Tyr Lys Gly     #               180     - ACG TGG AAC TTC ATC ACT GCA ACT GAA AAT GG - #C AAA CGT TAT TCT TTG      750     Thr Trp Asn Phe Ile Thr Ala Thr Glu Asn Gl - #y Lys Arg Tyr Ser Leu     #           195     - TTC AGT AAT TCT ATC GGT CAA GCT TAT TCC AG - #A CGC AGC GCT ATT TCA      798     Phe Ser Asn Ser Ile Gly Gln Ala Tyr Ser Ar - #g Arg Ser Ala Ile Ser     #       210     - GAA GAT ATC TAT AAT TTA GAA AAC GGT GAC GC - #G GGC TTA ATA AGT GAA      846     Glu Asp Ile Tyr Asn Leu Glu Asn Gly Asp Al - #a Gly Leu Ile Ser Glu     #   225     - TTT AGT GTA GAT TTT GGT AAG AAA GAG CTC AC - #T GGA GAA CTT TAT TAT      894     Phe Ser Val Asp Phe Gly Lys Lys Glu Leu Th - #r Gly Glu Leu Tyr Tyr     230                 2 - #35                 2 - #40                 2 -     #45     - AAT GAA AGG AAA ACA AGT GTT AAT GAA TCA CA - #A AAT ACA ACA CAT AAA      942     Asn Glu Arg Lys Thr Ser Val Asn Glu Ser Gl - #n Asn Thr Thr His Lys     #               260     - CTC TAC ACT CTA GAA GCT AAA GTG TAT AGC AA - #C CGA TTC AGA GGT AAA      990     Leu Tyr Thr Leu Glu Ala Lys Val Tyr Ser As - #n Arg Phe Arg Gly Lys     #           275     - GTA AAG CCA ACC AAA ACA AAG TCT GAA GAT CA - #T CCC TTT ACC AGC GAG     1038     Val Lys Pro Thr Lys Thr Lys Ser Glu Asp Hi - #s Pro Phe Thr Ser Glu     #       290     - GGA ACA TTA GAA GGT GGT TTT TAT GGG CCT AA - #T GCT GAA GAA CTA GGG     1086     Gly Thr Leu Glu Gly Gly Phe Tyr Gly Pro As - #n Ala Glu Glu Leu Gly     #   305     - GGA AAG TTT TTA GCT AAC GAC GAA AAA GTT TT - #T GGG GTA TTT AGT GCC     1134     Gly Lys Phe Leu Ala Asn Asp Glu Lys Val Ph - #e Gly Val Phe Ser Ala     310                 3 - #15                 3 - #20                 3 -     #25     - AAA GAA GAC CCA CAA AAC CCA GAA AAC CAA AA - #A TTA TCC ACA GAA ACC     1182     Lys Glu Asp Pro Gln Asn Pro Glu Asn Gln Ly - #s Leu Ser Thr Glu Thr     #               340     - TTA ATT GAT GGC AAG CTA ATT ACT TTT AAA AG - #A ACT GAT GCA ACA ACC     1230     Leu Ile Asp Gly Lys Leu Ile Thr Phe Lys Ar - #g Thr Asp Ala Thr Thr     #           355     - AAT GCA ACA ACC GAT GCA AAA ACC AGT GCA AC - #A ACC GAT GCA ACC AGT     1278     Asn Ala Thr Thr Asp Ala Lys Thr Ser Ala Th - #r Thr Asp Ala Thr Ser     #       370     - ACA ACA GCC AAT AAA AAA ACC GAT GCA GAA AA - #C TTT AAG ACG GAA GAT     1326     Thr Thr Ala Asn Lys Lys Thr Asp Ala Glu As - #n Phe Lys Thr Glu Asp     #   385     - ATA CCA AGT TTT GGT GAA GCT GAT TAC CTT TT - #A ATT GGC AAT CAG CCT     1374     Ile Pro Ser Phe Gly Glu Ala Asp Tyr Leu Le - #u Ile Gly Asn Gln Pro     390                 3 - #95                 4 - #00                 4 -     #05     - ATT CCT CTT TTA CCT GAA AAA AAT ACT GAT GA - #T TTC ATA AGT AGT AAG     1422     Ile Pro Leu Leu Pro Glu Lys Asn Thr Asp As - #p Phe Ile Ser Ser Lys     #               420     - CAC CAT ACG GTA GGA GGT AAA ACC TAT AAA GT - #A GAA GCA TGT TGC AAG     1470     His His Thr Val Gly Gly Lys Thr Tyr Lys Va - #l Glu Ala Cys Cys Lys     #           435     - AAT CTA AGC TAT GTG AAA TTT GGT ATG TAT TA - #T GAG GAT AAA GAT AAG     1518     Asn Leu Ser Tyr Val Lys Phe Gly Met Tyr Ty - #r Glu Asp Lys Asp Lys     #       450     - GAC AAC AAA AAT GAA ACA GAC AAA GAA AAA GG - #C AAA GAA AAA CCA ACG     1566     Asp Asn Lys Asn Glu Thr Asp Lys Glu Lys Gl - #y Lys Glu Lys Pro Thr     #   465     - ACG ACA ACA TCT ATC AAC ACT TAT TAT CAA TT - #C TTA TTA GGT CTC CGT     1614     Thr Thr Thr Ser Ile Asn Thr Tyr Tyr Gln Ph - #e Leu Leu Gly Leu Arg     470                 4 - #75                 4 - #80                 4 -     #85     - ACT CCC AAG GAC GAA ATA CCT AAA GAA GGA AG - #T GCA AAA TAT CAT GGT     1662     Thr Pro Lys Asp Glu Ile Pro Lys Glu Gly Se - #r Ala Lys Tyr His Gly     #               500     - AAT TGG TTT GGT TAT ATT AGT GAT GGC GAG AC - #A TCT TAC TCC GCC AGT     1710     Asn Trp Phe Gly Tyr Ile Ser Asp Gly Glu Th - #r Ser Tyr Ser Ala Ser     #           515     - GGT GAT AAG GAA CGC AGT AAA AAT GCT GTC GC - #C GAG TTT GAT GTA AGT     1758     Gly Asp Lys Glu Arg Ser Lys Asn Ala Val Al - #a Glu Phe Asp Val Ser     #       530     - TTT GCC AAT AAA ACA TTA ACA GGC GAA TTA AA - #A CGA CAC GAT AAT GGA     1806     Phe Ala Asn Lys Thr Leu Thr Gly Glu Leu Ly - #s Arg His Asp Asn Gly     #   545     - AAT ACC GTA TTT AAA ATT AAT GCA GAA TTA AA - #T GGT AGT AAT GAC TTC     1854     Asn Thr Val Phe Lys Ile Asn Ala Glu Leu As - #n Gly Ser Asn Asp Phe     550                 5 - #55                 5 - #60                 5 -     #65     - ACT GGT ACA GCA ACC GCA ACA AAT TTT GTA AT - #A GAT GGT AAC AAT AGT     1902     Thr Gly Thr Ala Thr Ala Thr Asn Phe Val Il - #e Asp Gly Asn Asn Ser     #               580     - CAA ACT TCA AAT GCC AAA ATT AAT ATT ACA AC - #T AAA GTA AAT GGG GCA     1950     Gln Thr Ser Asn Ala Lys Ile Asn Ile Thr Th - #r Lys Val Asn Gly Ala     #           595     - TTT TAT GGA CCT AAG GCT TCT GAA TTA GGA GG - #G TAT TTC ACC TAT AAC     1998     Phe Tyr Gly Pro Lys Ala Ser Glu Leu Gly Gl - #y Tyr Phe Thr Tyr Asn     #       610     - GGA AAA AAT CCT ACA GCT ACA AAT TCT GAA AG - #T TCC TCA ACC GTA CCT     2046     Gly Lys Asn Pro Thr Ala Thr Asn Ser Glu Se - #r Ser Ser Thr Val Pro     #   625     - TCA CCA CCC AAT TCA CCA AAT GCA AGC GCT GC - #A GTT GTC TTT GGT GCT     2094     Ser Pro Pro Asn Ser Pro Asn Ala Ser Ala Al - #a Val Val Phe Gly Ala     630                 6 - #35                 6 - #40                 6 -     #45     - AAA AAA CAA GTA GAA ACA ACC AAC AAG TAAAAACAA - #C CAAGTAATGG     2141     Lys Lys Gln Val Glu Thr Thr Asn Lys                     650     - AATACTAAAA ATG ACT AAA AAA CCC TAT TTT CGC CT - #A AGT ATT ATT TCT     2190     #Pro Tyr Phe Arg Leu Ser Ile Ile Ser     #          665     - TGT CTT TTA ATT TCA TGC TAT GTA AAA GCA GA - #A ACT CAA AGT ATA AAA     2238     Cys Leu Leu Ile Ser Cys Tyr Val Lys Ala Gl - #u Thr Gln Ser Ile Lys     #       680     - GAT ACA AAA GAA GCT ATA TCA TCT GAA GTG GA - #C ACT CAA AGT ACA GAA     2286     Asp Thr Lys Glu Ala Ile Ser Ser Glu Val As - #p Thr Gln Ser Thr Glu     #   695     - GAT TCA GAA TTA GAA ACT ATC TCA GTC ACT GC - #A GAA AAA ATA AGA GAT     2334     Asp Ser Glu Leu Glu Thr Ile Ser Val Thr Al - #a Glu Lys Ile Arg Asp     700                 7 - #05                 7 - #10                 7 -     #15     - CGT AAA GAT AAT GAA GTA ACT GGA CTT GGC AA - #A ATT ATC AAA ACT AGT     2382     Arg Lys Asp Asn Glu Val Thr Gly Leu Gly Ly - #s Ile Ile Lys Thr Ser     #               730     - GAA AGT ATC AGC CGA GAA CAA GTA TTA AAT AT - #T CGT GAT CTA ACA CGC     2430     Glu Ser Ile Ser Arg Glu Gln Val Leu Asn Il - #e Arg Asp Leu Thr Arg     #           745     - TAT GAT CCA GGC ATT TCA GTT GTA GAA CAA GG - #C CGT GGT GCA AGT TCT     2478     Tyr Asp Pro Gly Ile Ser Val Val Glu Gln Gl - #y Arg Gly Ala Ser Ser     #       760     - GGA TAT TCT ATT CGT GGT ATG GAC AGA AAT AG - #A GTT GCT TTA TTA GTA     2526     Gly Tyr Ser Ile Arg Gly Met Asp Arg Asn Ar - #g Val Ala Leu Leu Val     #   775     - GAT GGT TTA CCT CAA ACG CAA TCT TAT GTA GT - #G CAA AGC CCT TTA GTT     2574     Asp Gly Leu Pro Gln Thr Gln Ser Tyr Val Va - #l Gln Ser Pro Leu Val     780                 7 - #85                 7 - #90                 7 -     #95     - GCT CGT TCA GGA TAT TCT GGC ACT GGT GCA AT - #T AAT GAA ATT GAA TAT     2622     Ala Arg Ser Gly Tyr Ser Gly Thr Gly Ala Il - #e Asn Glu Ile Glu Tyr     #               810     - GAA AAT GTA AAG GCC GTC GAA ATA AGC AAG GG - #G GGG AGT TCT TCT GAG     2670     Glu Asn Val Lys Ala Val Glu Ile Ser Lys Gl - #y Gly Ser Ser Ser Glu     #           825     - TAT GGT AAT GGA GCA CTA GCT GGT TCT GTA AC - #A TTT CAA AGC AAA TCA     2718     Tyr Gly Asn Gly Ala Leu Ala Gly Ser Val Th - #r Phe Gln Ser Lys Ser     #       840     - GCA GCC GAT ATC TTA GAA GGA GAC AAA TCA TG - #G GGA ATT CAA ACT AAA     2766     Ala Ala Asp Ile Leu Glu Gly Asp Lys Ser Tr - #p Gly Ile Gln Thr Lys     #   855     - AAT GCT TAT TCA AGC AAA AAT AAA GGC TTT AC - #C CAT TCT TTA GCT GTA     2814     Asn Ala Tyr Ser Ser Lys Asn Lys Gly Phe Th - #r His Ser Leu Ala Val     860                 8 - #65                 8 - #70                 8 -     #75     - GCT GGA AAA CAA GGG GGA TTT GAC GGG GTC GC - #C ATT TAT ACT CAA CGA     2862     Ala Gly Lys Gln Gly Gly Phe Asp Gly Val Al - #a Ile Tyr Thr Gln Arg     #               890     - AAT TCA ATT GAA ACC CAA GTC CAT AAA GAT GC - #A TTA AAA GGC GTA CAA     2910     Asn Ser Ile Glu Thr Gln Val His Lys Asp Al - #a Leu Lys Gly Val Gln     #           905     - AGT TAT CAT CGA TTA ATC GCC AAA CCA GAG GA - #T CAA TCT GCA TAC TTT     2958     Ser Tyr His Arg Leu Ile Ala Lys Pro Glu As - #p Gln Ser Ala Tyr Phe     #       920     - GTG ATG CAA GAT GAG TGT CCA AAG CCA GAT GA - #T TAT AAC AGT TGT TTA     3006     Val Met Gln Asp Glu Cys Pro Lys Pro Asp As - #p Tyr Asn Ser Cys Leu     #   935     - CCT TTC GCC AAA CGA CCT GCG ATT TTA TCC TC - #C CAA AGA GAA ACC GTA     3054     Pro Phe Ala Lys Arg Pro Ala Ile Leu Ser Se - #r Gln Arg Glu Thr Val     940                 9 - #45                 9 - #50                 9 -     #55     - AGC GTT TCA GAT TAT ACG GGG GCT AAC CGT AT - #C AAA CCT AAT CCA ATG     3102     Ser Val Ser Asp Tyr Thr Gly Ala Asn Arg Il - #e Lys Pro Asn Pro Met     #               970     - AAA TAT GAA AGC CAG TCT TGG TTT TTA AGA GG - #A GGG TAT CAT TTT TCT     3150     Lys Tyr Glu Ser Gln Ser Trp Phe Leu Arg Gl - #y Gly Tyr His Phe Ser     #           985     - GAA CAA CAT TAT ATT GGT GGT ATT TTT GAA TT - #C ACA CAA CAA AAA TTT     3198     Glu Gln His Tyr Ile Gly Gly Ile Phe Glu Ph - #e Thr Gln Gln Lys Phe     #       1000     - GAT ATC CGT GAT ATG ACA TTT CCC GCT TAT TT - #A AGA TCA ACA GAA AAA     3246     Asp Ile Arg Asp Met Thr Phe Pro Ala Tyr Le - #u Arg Ser Thr Glu Lys     #  10150     - CGG GAT GAT AGC AGT GGC TCT TTT TAT CCA AA - #G CAA GAT TAT GGT GCA     3294     Arg Asp Asp Ser Ser Gly Ser Phe Tyr Pro Ly - #s Gln Asp Tyr Gly Ala     #               10351025 - #                1030     - TAT CAA CGT ATT GAG GAT GGC CGA GGC GTT AA - #C TAT GCA AGT GGG CTT     3342     Tyr Gln Arg Ile Glu Asp Gly Arg Gly Val As - #n Tyr Ala Ser Gly Leu     #              10505     - TAT TTC GAT GAA CAC CAT AGA AAA CAG CGT GT - #A GGT ATT GAA TAT ATT     3390     Tyr Phe Asp Glu His His Arg Lys Gln Arg Va - #l Gly Ile Glu Tyr Ile     #          10650     - TAC GAA AAT AAG AAC AAA GCG GGC ATC ATT GA - #C AAA GCA GTG TTA AGT     3438     Tyr Glu Asn Lys Asn Lys Ala Gly Ile Ile As - #p Lys Ala Val Leu Ser     #      10805     - GCT AAT CAA CAA AAC ATC ATA CTT GAC AGT TA - #T ATG CAA CAT ACG CAT     3486     Ala Asn Gln Gln Asn Ile Ile Leu Asp Ser Ty - #r Met Gln His Thr His     #  10950     - TGC AGT CTT TAT CCT AAT CCA AGT AAG AAT TG - #C CGC CCA ACA CGT GAT     3534     Cys Ser Leu Tyr Pro Asn Pro Ser Lys Asn Cy - #s Arg Pro Thr Arg Asp     #               11151105 - #                1110     - AAA CCT TAT TCA TAC TAT CAT TCT GAT AGA AA - #T GTT TAT AAA GAA AAA     3582     Lys Pro Tyr Ser Tyr Tyr His Ser Asp Arg As - #n Val Tyr Lys Glu Lys     #              11305     - CAT AAT ATG TTG CAA TTG AAT TTA GAG AAA AA - #A ATT CAA CAA AAT TGG     3630     His Asn Met Leu Gln Leu Asn Leu Glu Lys Ly - #s Ile Gln Gln Asn Trp     #          11450     - CTT ACT CAT CAA ATT GTC TTC AAT CTT GGT TT - #T GAT GAC TTT ACT TCA     3678     Leu Thr His Gln Ile Val Phe Asn Leu Gly Ph - #e Asp Asp Phe Thr Ser     #      11605     - GCG CTT CAG CAT AAA GAT TAT TTA ACT CGA CG - #T GTT ACC GCT ACG GCA     3726     Ala Leu Gln His Lys Asp Tyr Leu Thr Arg Ar - #g Val Thr Ala Thr Ala     #  11750     - AAG AGT ATT TCA GAG AAA GCT AAT GAA ACA AG - #A AGA AAT GGT TAC AAA     3774     Lys Ser Ile Ser Glu Lys Ala Asn Glu Thr Ar - #g Arg Asn Gly Tyr Lys     #               11951185 - #                1190     - AAA CAA CCT TAC TTA TAC CCA AAA CCA ACA GT - #A GGT TTT GTA GTA CAA     3822     Lys Gln Pro Tyr Leu Tyr Pro Lys Pro Thr Va - #l Gly Phe Val Val Gln     #              12105     - GAT CAT TGT GAT TAT AAA GGT AAC TCC TCT AA - #T TAC AGA GAC TGT AAA     3870     Asp His Cys Asp Tyr Lys Gly Asn Ser Ser As - #n Tyr Arg Asp Cys Lys     #          12250     - GTG CGG TTA ATT AAA GGG AAA AAT TAT TAT TT - #C GCA GCA CGC AAT AAT     3918     Val Arg Leu Ile Lys Gly Lys Asn Tyr Tyr Ph - #e Ala Ala Arg Asn Asn     #      12405     - ATG GCA TTA GGG AAA TAC GTT GAT TTA GGT TT - #A GGT ATT CGG TAT GAC     3966     Met Ala Leu Gly Lys Tyr Val Asp Leu Gly Le - #u Gly Ile Arg Tyr Asp     #  12550     - GTA TCT CGC ACA AAA GCT AAT GAA TCA ACT AT - #T AGT GTT GGT AAA TTT     4014     Val Ser Arg Thr Lys Ala Asn Glu Ser Thr Il - #e Ser Val Gly Lys Phe     #               12751265 - #                1270     - AAA AAT TTC TCT TGG AAT ACT GGT ATT GTC AT - #A AAA CCA ACG GAA TGG     4062     Lys Asn Phe Ser Trp Asn Thr Gly Ile Val Il - #e Lys Pro Thr Glu Trp     #              12905     - CTT GAT CTT TCT TAT CGC CTT TCT ACT GGA TT - #T AGA AAT CCT AGT TTT     4110     Leu Asp Leu Ser Tyr Arg Leu Ser Thr Gly Ph - #e Arg Asn Pro Ser Phe     #          13050     - GCT GAA ATG TAT GGT TGG CGG TAT GGT GGC AA - #T AAT AGC GAG GTT TAT     4158     Ala Glu Met Tyr Gly Trp Arg Tyr Gly Gly As - #n Asn Ser Glu Val Tyr     #      13205     - GTA GGT AAA TTT AAG CCT GAA ACA TCT CGT AA - #C CAA GAG TTT GGT CTC     4206     Val Gly Lys Phe Lys Pro Glu Thr Ser Arg As - #n Gln Glu Phe Gly Leu     #  13350     - GCT CTA AAA GGG GAT TTT GGT AAT ATT GAG AT - #C AGT CAT TTT AGT AAT     4254     Ala Leu Lys Gly Asp Phe Gly Asn Ile Glu Il - #e Ser His Phe Ser Asn     #               13551345 - #                1350     - GCT TAT CGA AAT CTT ATC GCC TTT GCT GAA GA - #A CTT AAT AAA AAT GGA     4302     Ala Tyr Arg Asn Leu Ile Ala Phe Ala Glu Gl - #u Leu Asn Lys Asn Gly     #              13705     - ACT GGA AAG GCC AAT TAT GGA TAT CAT AAT GC - #A CAA AAT GCA AAA TTA     4350     Thr Gly Lys Ala Asn Tyr Gly Tyr His Asn Al - #a Gln Asn Ala Lys Leu     #          13850     - GTT GGC GTA AAT ATA ACT GCG CAA TTA GAT TT - #T AAT GGT TTA TGG AAA     4398     Val Gly Val Asn Ile Thr Ala Gln Leu Asp Ph - #e Asn Gly Leu Trp Lys     #      14005     - CGT ATT CCC TAC GGT TGG TAT GCA ACA TTT GC - #T TAT AAC CGA GTA AAA     4446     Arg Ile Pro Tyr Gly Trp Tyr Ala Thr Phe Al - #a Tyr Asn Arg Val Lys     #  14150     - GTT AAA GAT CAA AAA ATC AAT GCT GGT TTG GC - #C TCC GTA AGC AGT TAT     4494     Val Lys Asp Gln Lys Ile Asn Ala Gly Leu Al - #a Ser Val Ser Ser Tyr     #               14351425 - #                1430     - TTA TTT GAT GCC ATT CAG CCC AGC CGT TAT AT - #C ATT GGT TTA GGC TAT     4542     Leu Phe Asp Ala Ile Gln Pro Ser Arg Tyr Il - #e Ile Gly Leu Gly Tyr     #              14505     - GAT CAT CCA AGT AAT ACT TGG GGA ATT AAT AC - #A ATG TTT ACT CAA TCA     4590     Asp His Pro Ser Asn Thr Trp Gly Ile Asn Th - #r Met Phe Thr Gln Ser     #          14650     - AAA GCA AAA TCT CAA AAT GAA TTG CTA GGA AA - #A CGT GCA TTG GGT AAC     4638     Lys Ala Lys Ser Gln Asn Glu Leu Leu Gly Ly - #s Arg Ala Leu Gly Asn     #      14805     - AAT TCA AGG GAT GTA AAA TCA ACA AGA AAA CT - #T ACT CGG GCA TGG CAT     4686     Asn Ser Arg Asp Val Lys Ser Thr Arg Lys Le - #u Thr Arg Ala Trp His     #  14950     - ATC TTA GAT GTA TCG GGT TAT TAC ATG GCG AA - #T AAA AAT ATT ATG CTT     4734     Ile Leu Asp Val Ser Gly Tyr Tyr Met Ala As - #n Lys Asn Ile Met Leu     #               15151505 - #                1510     - CGA TTA GGG ATA TAT AAT TTA TTC AAC TAT CG - #C TAT GTT ACT TGG GAA     4782     Arg Leu Gly Ile Tyr Asn Leu Phe Asn Tyr Ar - #g Tyr Val Thr Trp Glu     #              15305     - GCG GTG CGT CAA ACA GCA CAA GGT GCG GTC AA - #T CAA CAT CAA AAT GTT     4830     Ala Val Arg Gln Thr Ala Gln Gly Ala Val As - #n Gln His Gln Asn Val     #          15450     - GGT AGC TAT ACT CGC TAC GCA GCA TCA GGA CG - #A AAC TAT ACC TTA ACA     4878     Gly Ser Tyr Thr Arg Tyr Ala Ala Ser Gly Ar - #g Asn Tyr Thr Leu Thr     #      15605     - TTA GAA ATG AAA TTCTAAATTA AAATGCGCCA GATGGACTAG AC - #ATGCTATA     4930     Leu Glu Met Lys         1565     - TCTATACCTT ACTGGCGCAT CTTTTTCTGT TCTATAATCT GGTTAAGTGA AA - #AACCAAAC     4990     - TTGGATTTTT TAGAAGATCT TTCCACGCAT TTATTGTAAA ATCTCCGACA AT - #TTTTACCG     5050     #             5099CAAAA ACAATAAGGA TCCTTTTGTG AATCTCTCA     - (2) INFORMATION FOR SEQ ID NO:5:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 913 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:5: (xi) SEQUENCE DESCRIPTION: SEQ     -      Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys Leu     Leu     #   15     -      Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp Thr     Lys     #                 30     -      Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp Ser     Glu     #             45     -      Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Val Arg Asp Arg Lys     Asp     #         60     -      Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu Ser     Ile     #     80     -      Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr Asp     Pro     #   95     -      Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly Tyr     Ser     #                110     -      Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp Gly     Leu     #            125     -      Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala Arg     Ser     #        140     -      Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu Asn     Val     #    160     -      Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr Gly     Asn     #   175     -      Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala Ala     Asp     #                190     -      Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn Ala     Tyr     #            205     -      Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala Gly     Lys     #        220     -      Gln Gly Gly Phe Glu Gly Val Ala - # Ile Tyr Thr His Arg Asn Ser     Ile     #    240     -      Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser Tyr     Asp     #   255     -      Arg Phe Ile Ala Thr Thr Glu Asp - # Gln Ser Ala Tyr Phe Val Met     Gln     #                270     -      Asp Glu Cys Leu Asp Gly Tyr Asp - # Lys Cys Lys Thr Ser Pro Lys     Arg     #            285     -      Pro Ala Thr Leu Ser Thr Gln Arg - # Glu Thr Val Ser Val Ser Asp     Tyr     #        300     -      Thr Gly Ala Asn Arg Ile Lys Pro - # Asn Pro Met Lys Tyr Glu Ser     Gln     #    320     -      Ser Trp Phe Leu Arg Gly Gly Tyr - # His Phe Ser Glu Gln His Tyr     Ile     #   335     -      Gly Gly Ile Phe Glu Phe Thr Gln - # Gln Lys Phe Asp Ile Arg Asp     Met     #                350     -      Thr Phe Pro Ala Tyr Leu Arg Pro - # Thr Glu Asp Lys Asp Leu Gln     Ser     #            365     -      Arg Pro Phe Tyr Pro Lys Gln Asp - # Tyr Gly Ala Tyr Gln His Ile     Gly     #        380     -      Asp Gly Arg Gly Val Lys Tyr Ala - # Ser Gly Leu Tyr Phe Asp Glu     His     #    400     -      His Arg Lys Gln Arg Val Gly Ile - # Glu Tyr Ile Tyr Glu Asn Lys     Asn     #   415     -      Lys Ala Gly Ile Ile Asp Lys Ala - # Val Leu Ser Ala Asn Gln Gln     Asn     #                430     -      Ile Ile Leu Asp Ser Tyr Met Arg - # His Thr His Cys Ser Leu Tyr     Pro     #            445     -      Asn Pro Ser Lys Asn Cys Arg Pro - # Thr Leu Asp Lys Pro Tyr Ser     Tyr     #        460     -      Tyr His Ser Asp Arg Asn Val Tyr - # Lys Glu Lys His Asn Met Leu     Gln     #    480     -      Leu Asn Leu Glu Lys Lys Ile Gln - # Gln Asn Trp Leu Thr His Gln     Ile     #   495     -      Ala Phe Asn Leu Gly Phe Asp Asp - # Phe Thr Ser Ala Leu Gln His     Lys     #                510     -      Asp Tyr Leu Thr Arg Arg Val Ile - # Ala Thr Ala Ser Ser Ile Ser     Glu     #            525     -      Lys Arg Gly Glu Ala Arg Arg Asn - # Gly Leu Gln Ser Ser Pro Tyr     Leu     #        540     -      Tyr Pro Thr Pro Lys Ala Glu Leu - # Val Gly Gly Asp Leu Cys Asn     Tyr     #    560     -      Gln Gly Lys Ser Ser Asn Tyr Ser - # Asp Cys Lys Val Arg Leu Ile     Lys     #   575     -      Gly Lys Asn Tyr Tyr Phe Ala Ala - # Arg Asn Asn Met Ala Leu Gly     Lys     #                590     -      Tyr Val Asp Leu Gly Leu Gly Met - # Arg Tyr Asp Val Ser Arg Thr     Lys     #            605     -      Ala Asn Glu Ser Thr Ile Ser Val - # Gly Lys Phe Lys Asn Phe Ser     Trp     #        620     -      Asn Thr Gly Ile Val Ile Lys Pro - # Thr Glu Trp Leu Asp Leu Ser     Tyr     #    640     -      Arg Leu Ser Thr Gly Phe Arg Asn - # Pro Ser Phe Ala Glu Met Tyr     Gly     #   655     -      Trp Arg Tyr Gly Gly Lys Asp Thr - # Asp Val Tyr Ile Gly Lys Phe     Lys     #                670     -      Pro Glu Thr Ser Arg Asn Gln Glu - # Phe Gly Leu Ala Leu Lys Gly     Asp     #            685     -      Phe Gly Asn Ile Glu Ile Ser His - # Phe Ser Asn Ala Tyr Arg Asn     Leu     #        700     -      Ile Ala Phe Ala Glu Glu Leu Ser - # Lys Asn Gly Thr Thr Gly Lys     Gly     #    720     -      Asn Tyr Gly Tyr His Asn Ala Gln - # Asn Ala Lys Leu Val Gly Val     Asn     #   735     -      Ile Thr Ala Gln Leu Asp Phe Asn - # Gly Leu Trp Lys Arg Ile Pro     Tyr     #                750     -      Gly Trp Tyr Ala Thr Phe Ala Tyr - # Asn Arg Val Lys Val Lys Asp     Gln     #            765     -      Lys Ile Asn Ala Gly Leu Ala Ser - # Val Ser Ser Tyr Leu Phe Asp     Ala     #        780     -      Ile Gln Pro Ser Arg Tyr Ile Ile - # Gly Leu Gly Tyr Asp His Pro     Ser     #    800     -      Asn Thr Trp Gly Ile Lys Thr Met - # Phe Thr Gln Ser Lys Ala Lys     Ser     #   815     -      Gln Asn Glu Leu Leu Gly Lys Arg - # Ala Leu Gly Asn Asn Ser Arg     Asn     #                830     -      Val Lys Ser Thr Arg Lys Leu Thr - # Arg Ala Trp His Ile Leu Asp     Val     #            845     -      Ser Gly Tyr Tyr Met Val Asn Arg - # Ser Ile Leu Phe Arg Leu Gly     Val     #        860     -      Tyr Asn Leu Leu Asn Tyr Arg Tyr - # Val Thr Trp Glu Ala Val Arg     Gln     #    880     -      Thr Ala Gln Gly Ala Val Asn Gln - # His Gln Asn Val Gly Asn Tyr     Thr     #   895     -      Arg Tyr Ala Ala Ser Gly Arg Asn - # Tyr Thr Leu Thr Leu Glu Met     Lys     #                910     -      Phe     - (2) INFORMATION FOR SEQ ID NO:6:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 644 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:6: (xi) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu Leu     Ser     #   15     -      Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser Asn     Thr     #                 30     -      Pro Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Ser Ser Arg     Thr     #             45     -      Lys Ser Lys Leu Glu Lys Leu Ser - # Ile Pro Ser Leu Gly Gly Gly     Met     #         60     -      Lys Leu Ala Ala Leu Asn Leu Phe - # Asp Arg Asn Lys Pro Ser Leu     Leu     #     80     -      Asn Glu Asp Ser Tyr Met Ile Phe - # Ser Ser Arg Ser Thr Ile Glu     Glu     #   95     -      Asp Val Lys Asn Asp Asn Gln Asn - # Gly Glu His Pro Ile Asp Ser     Ile     #                110     -      Val Asp Pro Arg Ala Pro Asn Ser - # Asn Glu Asn Arg His Gly Gln     Lys     #            125     -      Tyr Val Tyr Ser Gly Leu Tyr Tyr - # Ile Gln Ser Trp Ser Leu Arg     Asp     #        140     -      Leu Pro Asn Lys Lys Phe Tyr Ser - # Gly Tyr Tyr Gly Tyr Ala Tyr     Tyr     #    160     -      Phe Gly Asn Thr Thr Ala Ser Ala - # Leu Pro Val Gly Gly Val Ala     Thr     #   175     -      Tyr Lys Gly Thr Trp Ser Phe Ile - # Thr Ala Ala Glu Asn Gly Lys     Asn     #                190     -      Tyr Glu Leu Leu Arg Asn Ser Gly - # Gly Gly Gln Ala Tyr Ser Arg     Arg     #            205     -      Ser Ala Thr Pro Glu Asp Ile Asp - # Leu Asp Arg Lys Thr Gly Leu     Thr     #        220     -      Ser Glu Phe Thr Val Asn Phe Gly - # Thr Lys Lys Leu Thr Gly Gly     Leu     #    240     -      Tyr Tyr Asn Leu Arg Glu Thr Asp - # Ala Asn Lys Ser Gln Asn Arg     Thr     #   255     -      His Lys Leu Tyr Asp Leu Glu Ala - # Asp Val His Ser Asn Arg Phe     Arg     #                270     -      Gly Lys Val Lys Pro Thr Lys Lys - # Glu Ser Ser Glu Glu His Pro     Phe     #            285     -      Thr Ser Glu Gly Thr Leu Glu Gly - # Gly Phe Tyr Gly Pro Glu Gly     Gln     #        300     -      Glu Leu Gly Gly Lys Phe Leu Ala - # His Asp Lys Lys Val Leu Gly     Val     #    320     -      Phe Ser Ala Lys Glu Gln Gln Glu - # Thr Ser Glu Asn Lys Lys Leu     Pro     #   335     -      Lys Glu Thr Leu Ile Asp Gly Lys - # Leu Thr Thr Phe Lys Thr Thr     Asn     #                350     -      Ala Thr Ala Asn Ala Thr Thr Asp - # Ala Thr Thr Ser Thr Thr Ala     Ser     #            365     -      Thr Lys Thr Asp Thr Thr Thr Asn - # Ala Thr Ala Asn Thr Glu Asn     Phe     #        380     -      Thr Thr Lys Asp Ile Pro Ser Leu - # Gly Glu Ala Asp Tyr Leu Leu     Ile     #    400     -      Asp Asn Tyr Pro Val Pro Leu Phe - # Pro Glu Ser Gly Asp Phe Ile     Ser     #   415     -      Ser Lys His His Thr Val Gly Lys - # Lys Thr Tyr Gln Val Glu Ala     Cys     #                430     -      Cys Ser Asn Leu Ser Tyr Val Lys - # Phe Gly Met Tyr Tyr Glu Ala     Pro     #            445     -      Pro Lys Glu Glu Glu Lys Glu Lys - # Glu Lys Asp Lys Asp Lys Glu     Lys     #        460     -      Glu Lys Gln Ala Thr Thr Ser Ile - # Lys Thr Tyr Tyr Gln Phe Leu     Leu     #    480     -      Gly Leu Arg Thr Pro Ser Ser Glu - # Ile Pro Lys Glu Gly Ser Ala     Lys     #   495     -      Tyr His Gly Asn Trp Phe Gly Tyr - # Ile Ser Asp Gly Glu Thr Ser     Tyr     #                510     -      Ser Ala Ser Gly Asp Lys Glu Arg - # Ser Lys Asn Ala Val Ala Glu     Phe     #            525     -      Asn Val Asn Phe Ala Glu Lys Thr - # Leu Thr Gly Glu Leu Lys Arg     His     #        540     -      Asp Thr Gln Asn Pro Val Phe Lys - # Ile Asn Ala Thr Phe Gln Ser     Gly     #    560     -      Lys Asn Asp Phe Thr Gly Thr Ala - # Thr Ala Lys Asp Leu Ala Ile     Asp     #   575     -      Gly Lys Asn Thr Gln Gly Thr Ser - # Lys Val Asn Phe Thr Ala Thr     Val     #                590     -      Asn Gly Ala Phe Tyr Gly Pro His - # Ala Thr Glu Leu Gly Gly Tyr     Phe     #            605     -      Thr Tyr Asn Gly Asn Asn Pro Thr - # Asp Lys Asn Ser Ser Ser Asn     Ser     #        620     -      Glu Lys Ala Arg Ala Ala Val Val - # Phe Gly Ala Lys Lys Gln Gln     Val     #    640     -      Glu Thr Thr Lys     - (2) INFORMATION FOR SEQ ID NO:7:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 912 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:7: (xi) SEQUENCE DESCRIPTION: SEQ     -      Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys Leu     Leu     #   15     -      Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp Thr     Lys     #                 30     -      Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp Ser     Glu     #             45     -      Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Ile Arg Asp Arg Lys     Asp     #         60     -      Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu Ser     Ile     #     80     -      Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr Asp     Pro     #   95     -      Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly Tyr     Ser     #                110     -      Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp Gly     Leu     #            125     -      Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala Arg     Ser     #        140     -      Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu Asn     Val     #    160     -      Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr Gly     Asn     #   175     -      Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala Ala     Asp     #                190     -      Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn Ala     Tyr     #            205     -      Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala Gly     Lys     #        220     -      Gln Gly Gly Phe Glu Gly Leu Ala - # Ile Tyr Thr Gln Arg Asn Ser     Ile     #    240     -      Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser Tyr     Asp     #   255     -      Arg Leu Ile Ala Thr Thr Asp Lys - # Ser Ser Gly Tyr Phe Val Ile     Gln     #                270     -      Gly Glu Cys Pro Asn Gly Asp Asp - # Lys Cys Ala Ala Lys Pro Pro     Ala     #            285     -      Thr Leu Ser Thr Gln Ser Glu Thr - # Val Ser Val Ser Asp Tyr Thr     Gly     #        300     -      Ala Asn Arg Ile Lys Pro Asn Pro - # Met Lys Tyr Glu Ser Gln Ser     Trp     #    320     -      Phe Leu Arg Gly Gly Tyr His Phe - # Ser Glu Gln His Tyr Ile Gly     Gly     #   335     -      Ile Phe Glu Phe Thr Gln Gln Lys - # Phe Asp Ile Arg Asp Met Thr     Phe     #                350     -      Pro Ala Tyr Leu Ser Pro Thr Glu - # Arg Arg Asp Asp Ser Ser Arg     Ser     #            365     -      Phe Tyr Pro Met Gln Asp His Gly - # Ala Tyr Gln His Ile Glu Asp     Gly     #        380     -      Arg Gly Val Lys Tyr Ala Ser Gly - # Leu Tyr Phe Asp Glu His His     Arg     #    400     -      Lys Gln Arg Val Gly Ile Glu Tyr - # Ile Tyr Glu Asn Lys Asn Lys     Ala     #   415     -      Gly Ile Ile Asp Lys Ala Val Leu - # Ser Ala Asn Gln Gln Asn Ile     Ile     #                430     -      Leu Asp Ser Tyr Met Arg His Thr - # His Cys Ser Leu Tyr Pro Asn     Pro     #            445     -      Ser Lys Asn Cys Arg Pro Thr Leu - # Asp Lys Pro Tyr Ser Tyr Tyr     Arg     #        460     -      Ser Asp Arg Asn Val Tyr Lys Glu - # Lys His Asn Met Leu Gln Leu     Asn     #    480     -      Leu Glu Lys Lys Ile Gln Gln Asn - # Trp Leu Thr His Gln Ile Val     Phe     #   495     -      Asn Leu Gly Phe Asp Asp Phe Thr - # Ser Ala Leu Gln His Lys Asp     Tyr     #                510     -      Leu Thr Arg Arg Val Ile Ala Thr - # Ala Asp Ser Ile Pro Arg Lys     Pro     #            525     -      Gly Glu Thr Gly Lys Pro Arg Asn - # Gly Leu Gln Ser Gln Pro Tyr     Leu     #        540     -      Tyr Pro Lys Pro Glu Pro Tyr Phe - # Ala Gly Gln Asp His Cys Asn     Tyr     #    560     -      Gln Gly Ser Ser Ser Asn Tyr Arg - # Asp Cys Lys Val Arg Leu Ile     Lys     #   575     -      Gly Lys Asn Tyr Tyr Phe Ala Ala - # Arg Asn Asn Met Ala Leu Gly     Lys     #                590     -      Tyr Val Asp Leu Gly Leu Gly Ile - # Arg Tyr Asp Val Ser Arg Thr     Lys     #            605     -      Ala Asn Glu Ser Thr Ile Ser Val - # Gly Lys Phe Lys Asn Phe Ser     Trp     #        620     -      Asn Thr Gly Ile Val Ile Lys Pro - # Thr Glu Trp Leu Asp Leu Ser     Tyr     #    640     -      Arg Leu Ser Thr Gly Phe Arg Asn - # Pro Ser Phe Ser Glu Met Tyr     Gly     #   655     -      Trp Arg Tyr Gly Gly Lys Asn Asp - # Glu Val Tyr Val Gly Lys Phe     Lys     #                670     -      Pro Glu Thr Ser Arg Asn Gln Glu - # Phe Gly Leu Ala Leu Lys Gly     Asp     #            685     -      Phe Gly Asn Ile Glu Ile Ser His - # Phe Ser Asn Ala Tyr Arg Asn     Leu     #        700     -      Ile Ala Phe Ala Glu Glu Leu Ser - # Lys Asn Gly Thr Gly Lys Gly     Asn     #    720     -      Tyr Gly Tyr His Asn Ala Gln Asn - # Ala Lys Leu Val Gly Val Asn     Ile     #   735     -      Thr Ala Gln Leu Asp Phe Asn Gly - # Leu Trp Lys Arg Ile Pro Tyr     Gly     #                750     -      Trp Tyr Ala Thr Phe Ala Tyr Asn - # Gln Val Lys Val Lys Asp Gln     Lys     #            765     -      Ile Asn Ala Gly Leu Ala Ser Val - # Ser Ser Tyr Leu Phe Asp Ala     Ile     #        780     -      Gln Pro Ser Arg Tyr Ile Ile Gly - # Leu Gly Tyr Asp His Pro Ser     Asn     #    800     -      Thr Trp Gly Ile Asn Thr Met Phe - # Thr Gln Ser Lys Ala Lys Ser     Gln     #   815     -      Asn Glu Leu Leu Gly Lys Arg Ala - # Leu Gly Asn Asn Ser Arg Asp     Val     #                830     -      Lys Ser Thr Arg Lys Leu Thr Arg - # Ala Trp His Ile Leu Asp Val     Ser     #            845     -      Gly Tyr Tyr Met Ala Asn Lys Asn - # Ile Met Leu Arg Leu Gly Ile     Tyr     #        860     -      Asn Leu Phe Asn Tyr Arg Tyr Val - # Thr Trp Glu Ala Val Arg Gln     Thr     #    880     -      Ala Gln Gly Ala Val Asn Gln His - # Gln Asn Val Gly Ser Tyr Thr     Arg     #   895     -      Tyr Ala Ala Ser Gly Arg Asn Tyr - # Thr Leu Thr Leu Glu Met Lys     Phe     #                910     - (2) INFORMATION FOR SEQ ID NO:8:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 660 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:8: (xi) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu Leu     Ser     #   15     -      Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser Asn     Thr     #                 30     -      Pro Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Asn Gln Arg     Lys     #             45     -      Lys Ser Asn Leu Lys Lys Leu Phe - # Ile Pro Ser Leu Gly Gly Gly     Met     #         60     -      Lys Leu Val Ala Gln Asn Leu Arg - # Gly Asn Lys Glu Pro Ser Phe     Leu     #     80     -      Asn Glu Asp Asp Tyr Ile Ser Tyr - # Phe Ser Ser Leu Ser Thr Ile     Glu     #   95     -      Lys Asp Val Lys Asp Asn Asn Lys - # Asn Gly Ala Asp Leu Ile Gly     Ser     #                110     -      Ile Asp Glu Pro Ser Thr Thr Asn - # Pro Pro Glu Lys His His Gly     Gln     #            125     -      Lys Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Thr Pro Ser Trp Ser Leu     Asn     #        140     -      Asp Ser Lys Asn Lys Phe Tyr Leu - # Gly Tyr Tyr Gly Tyr Ala Phe     Tyr     #    160     -      Tyr Gly Asn Lys Thr Ala Thr Asn - # Leu Pro Val Asn Gly Val Ala     Lys     #   175     -      Tyr Lys Gly Thr Trp Asp Phe Ile - # Thr Ala Thr Lys Asn Gly Lys     Arg     #                190     -      Tyr Pro Leu Leu Ser Asn Gly Ser - # His Ala Tyr Tyr Arg Arg Ser     Ala     #            205     -      Ile Pro Glu Asp Ile Asp Leu Glu - # Asn Asp Ser Lys Asn Gly Asp     Ile     #        220     -      Gly Leu Ile Ser Glu Phe Ser Ala - # Asp Phe Gly Thr Lys Lys Leu     Thr     #    240     -      Gly Gln Leu Ser Tyr Thr Lys Arg - # Lys Thr Asn Asn Gln Pro Tyr     Glu     #   255     -      Lys Lys Lys Leu Tyr Asp Ile Asp - # Ala Asp Ile Tyr Ser Asn Arg     Phe     #                270     -      Arg Gly Thr Val Lys Pro Thr Glu - # Lys Asp Ser Glu Glu His Pro     Phe     #            285     -      Thr Ser Glu Gly Thr Leu Glu Gly - # Gly Phe Tyr Gly Pro Asn Ala     Glu     #        300     -      Glu Leu Gly Gly Lys Phe Leu Ala - # Thr Asp Asn Arg Val Phe Gly     Val     #    320     -      Phe Ser Ala Lys Glu Thr Glu Glu - # Thr Lys Lys Glu Ala Leu Ser     Lys     #   335     -      Glu Thr Leu Ile Asp Gly Lys Leu - # Ile Thr Phe Ser Thr Lys Lys     Thr     #                350     -      Asp Ala Lys Thr Asn Ala Thr Thr - # Ser Thr Ala Ala Asn Thr Thr     Thr     #            365     -      Asp Thr Thr Ala Asn Thr Ile Thr - # Asp Glu Lys Asn Phe Lys Thr     Glu     #        380     -      Asp Ile Ser Ser Phe Gly Glu Ala - # Asp Tyr Leu Leu Ile Asp Lys     Tyr     #    400     -      Pro Ile Pro Leu Leu Pro Asp Lys - # Asn Thr Asn Asp Phe Ile Ser     Ser     #   415     -      Lys His His Thr Val Gly Asn Lys - # Arg Tyr Lys Val Glu Ala Cys     Cys     #                430     -      Ser Asn Leu Ser Tyr Val Lys Phe - # Gly Met Tyr Tyr Glu Asp Pro     Leu     #            445     -      Lys Glu Lys Glu Thr Glu Thr Glu - # Thr Glu Thr Glu Lys Asp Lys     Glu     #        460     -      Lys Glu Lys Glu Lys Asp Lys Asp - # Lys Glu Lys Gln Thr Ala Ala     Thr     #    480     -      Thr Asn Thr Tyr Tyr Gln Phe Leu - # Leu Gly His Arg Thr Pro Lys     Asp     #   495     -      Asp Ile Pro Lys Thr Gly Ser Ala - # Lys Tyr His Gly Ser Trp Phe     Gly     #                510     -      Tyr Ile Thr Asp Gly Lys Thr Ser - # Tyr Ser Pro Ser Gly Asp Lys     Lys     #            525     -      Arg Asp Lys Asn Ala Val Ala Glu - # Phe Asn Val Asp Phe Ala Glu     Lys     #        540     -      Lys Leu Thr Gly Glu Leu Lys Arg - # His Asp Thr Gly Asn Pro Val     Phe     #    560     -      Ser Ile Glu Ala Asn Phe Asn Asn - # Ser Ser Asn Ala Phe Thr Gly     Thr     #   575     -      Ala Thr Ala Thr Asn Phe Val Ile - # Asp Gly Lys Asn Ser Gln Asn     Lys     #                590     -      Asn Thr Pro Ile Asn Ile Thr Thr - # Lys Val Asn Gly Ala Phe Tyr     Gly     #            605     -      Pro Lys Ala Ser Glu Leu Gly Gly - # Tyr Phe Thr Tyr Asn Gly Asn     Ser     #        620     -      Thr Ala Thr Asn Ser Glu Ser Ser - # Ser Thr Val Ser Ser Ser Ser     Asn     #    640     -      Ser Lys Asn Ala Arg Ala Ala Val - # Val Phe Gly Ala Arg Gln Gln     Val     #   655     -      Glu Thr Thr Lys                      660     - (2) INFORMATION FOR SEQ ID NO:9:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 912 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:9: (xi) SEQUENCE DESCRIPTION: SEQ     -      Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys Leu     Leu     #   15     -      Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp Thr     Lys     #                 30     -      Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp Ser     Glu     #             45     -      Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Ile Arg Asp Arg Lys     Asp     #         60     -      Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu Ser     Ile     #     80     -      Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr Asp     Pro     #   95     -      Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly Tyr     Ser     #                110     -      Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp Gly     Leu     #            125     -      Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala Arg     Ser     #        140     -      Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu Asn     Val     #    160     -      Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr Gly     Asn     #   175     -      Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala Ala     Asp     #                190     -      Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn Ala     Tyr     #            205     -      Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala Gly     Lys     #        220     -      Gln Gly Gly Phe Glu Gly Leu Ala - # Ile Tyr Thr Gln Arg Asn Ser     Ile     #    240     -      Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser Tyr     Asp     #   255     -      Arg Leu Ile Ala Thr Thr Asp Lys - # Ser Ser Gly Tyr Phe Val Ile     Gln     #                270     -      Gly Glu Cys Pro Asn Gly Asp Asp - # Lys Cys Ala Ala Lys Pro Pro     Ala     #            285     -      Thr Leu Ser Thr Gln Ser Glu Thr - # Val Ser Val Ser Asp Tyr Thr     Gly     #        300     -      Ala Asn Arg Ile Lys Pro Asn Pro - # Met Lys Tyr Glu Ser Gln Ser     Trp     #    320     -      Phe Leu Arg Gly Gly Tyr His Phe - # Ser Glu Gln His Tyr Ile Gly     Gly     #   335     -      Ile Phe Glu Phe Thr Gln Gln Lys - # Phe Asp Ile Arg Asp Met Thr     Phe     #                350     -      Pro Ala Tyr Leu Ser Pro Thr Glu - # Arg Arg Asp Asp Ser Ser Arg     Ser     #            365     -      Phe Tyr Pro Met Gln Asp His Gly - # Ala Tyr Gln His Ile Glu Asp     Gly     #        380     -      Arg Gly Val Lys Tyr Ala Ser Gly - # Leu Tyr Phe Asp Glu His His     Arg     #    400     -      Lys Gln Arg Val Gly Ile Glu Tyr - # Ile Tyr Glu Asn Lys Asn Lys     Ala     #   415     -      Gly Ile Ile Asp Lys Ala Val Leu - # Ser Ala Asn Gln Gln Asn Ile     Ile     #                430     -      Leu Asp Ser Tyr Met Arg His Thr - # His Cys Ser Leu Tyr Pro Asn     Pro     #            445     -      Ser Lys Asn Cys Arg Pro Thr Leu - # Asp Lys Pro Tyr Ser Tyr Tyr     Arg     #        460     -      Ser Asp Arg Asn Val Tyr Lys Glu - # Lys His Asn Met Leu Gln Leu     Asn     #    480     -      Leu Glu Lys Lys Ile Gln Gln Asn - # Trp Leu Thr His Gln Ile Val     Phe     #   495     -      Asn Leu Gly Phe Asp Asp Phe Thr - # Ser Ala Leu Gln His Lys Asp     Tyr     #                510     -      Leu Thr Arg Arg Val Ile Ala Thr - # Ala Asp Ser Ile Pro Arg Lys     Pro     #            525     -      Gly Glu Thr Gly Lys Pro Arg Asn - # Gly Leu Gln Ser Gln Pro Tyr     Leu     #        540     -      Tyr Pro Lys Pro Glu Pro Tyr Phe - # Ala Gly Gln Asp His Cys Asn     Tyr     #    560     -      Gln Gly Ser Ser Ser Asn Tyr Arg - # Asp Cys Lys Val Arg Leu Ile     Lys     #   575     -      Gly Lys Asn Tyr Tyr Phe Ala Ala - # Arg Asn Asn Met Ala Leu Gly     Lys     #                590     -      Tyr Val Asp Leu Gly Leu Gly Ile - # Arg Tyr Asp Val Ser Arg Thr     Lys     #            605     -      Ala Asn Glu Ser Thr Ile Ser Val - # Gly Lys Phe Lys Asn Phe Ser     Trp     #        620     -      Asn Thr Gly Ile Val Ile Lys Pro - # Thr Glu Trp Leu Asp Leu Ser     Tyr     #    640     -      Arg Leu Ser Thr Gly Phe Arg Asn - # Pro Ser Phe Ser Glu Met Tyr     Gly     #   655     -      Trp Arg Tyr Gly Gly Lys Asn Asp - # Glu Val Tyr Val Gly Lys Phe     Lys     #                670     -      Pro Glu Thr Ser Arg Asn Gln Glu - # Phe Gly Leu Ala Leu Lys Gly     Asp     #            685     -      Phe Gly Asn Ile Glu Ile Ser His - # Phe Ser Asn Ala Tyr Arg Asn     Leu     #        700     -      Ile Ala Phe Ala Glu Glu Leu Ser - # Lys Asn Gly Thr Gly Lys Gly     Asn     #    720     -      Tyr Gly Tyr His Asn Ala Gln Asn - # Ala Lys Leu Val Gly Val Asn     Ile     #   735     -      Thr Ala Gln Leu Asp Phe Asn Gly - # Leu Trp Lys Arg Ile Pro Tyr     Gly     #                750     -      Trp Tyr Ala Thr Phe Ala Tyr Asn - # Gln Val Lys Val Lys Asp Gln     Lys     #            765     -      Ile Asn Ala Gly Leu Ala Ser Val - # Ser Ser Tyr Leu Phe Asp Ala     Ile     #        780     -      Gln Pro Ser Arg Tyr Ile Ile Gly - # Leu Gly Tyr Asp His Pro Ser     Asn     #    800     -      Thr Trp Gly Ile Asn Thr Met Phe - # Thr Gln Ser Lys Ala Lys Ser     Gln     #   815     -      Asn Glu Leu Leu Gly Lys Arg Ala - # Leu Gly Asn Asn Ser Arg Asp     Val     #                830     -      Lys Ser Thr Arg Lys Leu Thr Arg - # Ala Trp His Ile Leu Asp Val     Ser     #            845     -      Gly Tyr Tyr Met Ala Asn Lys Asn - # Ile Met Leu Arg Leu Gly Ile     Tyr     #        860     -      Asn Leu Phe Asn Tyr Arg Tyr Val - # Thr Trp Glu Ala Val Arg Gln     Thr     #    880     -      Ala Gln Gly Ala Val Asn Gln His - # Gln Asn Val Gly Ser Tyr Thr     Arg     #   895     -      Tyr Ala Ala Ser Gly Arg Asn Tyr - # Thr Leu Thr Leu Glu Met Lys     Phe     #                910     - (2) INFORMATION FOR SEQ ID NO:10:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 660 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:10:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu Leu     Ser     #   15     -      Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser Asn     Thr     #                 30     -      Pro Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Asn Gln Arg     Lys     #             45     -      Lys Ser Asn Leu Lys Lys Leu Phe - # Ile Pro Ser Leu Gly Gly Gly     Met     #         60     -      Lys Leu Val Ala Gln Asn Leu Arg - # Gly Asn Lys Glu Pro Ser Phe     Leu     #     80     -      Asn Glu Asp Asp Tyr Ile Ser Tyr - # Phe Ser Ser Leu Ser Thr Ile     Glu     #   95     -      Lys Asp Val Lys Asp Asn Asn Lys - # Asn Gly Ala Asp Leu Ile Gly     Ser     #                110     -      Ile Asp Glu Pro Ser Thr Thr Asn - # Pro Pro Glu Lys His His Gly     Gln     #            125     -      Lys Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Thr Pro Ser Trp Ser Leu     Asn     #        140     -      Asp Ser Lys Asn Lys Phe Tyr Leu - # Gly Tyr Tyr Gly Tyr Ala Phe     Tyr     #    160     -      Tyr Gly Asn Lys Thr Ala Thr Asn - # Leu Pro Val Asn Gly Val Ala     Lys     #   175     -      Tyr Lys Gly Thr Trp Asp Phe Ile - # Thr Ala Thr Lys Asn Gly Lys     Arg     #                190     -      Tyr Pro Leu Leu Ser Asn Gly Ser - # His Ala Tyr Tyr Arg Arg Ser     Ala     #            205     -      Ile Pro Glu Asp Ile Asp Leu Glu - # Asn Asp Ser Lys Asn Gly Asp     Ile     #        220     -      Gly Leu Ile Ser Glu Phe Ser Ala - # Asp Phe Gly Thr Lys Lys Leu     Thr     #    240     -      Gly Gln Leu Ser Tyr Thr Lys Arg - # Lys Thr Asn Asn Gln Pro Tyr     Glu     #   255     -      Lys Lys Lys Leu Tyr Asp Ile Asp - # Ala Asp Ile Tyr Ser Asn Arg     Phe     #                270     -      Arg Gly Thr Val Lys Pro Thr Glu - # Lys Asp Ser Glu Glu His Pro     Phe     #            285     -      Thr Ser Glu Gly Thr Leu Glu Gly - # Gly Phe Tyr Gly Pro Asn Ala     Glu     #        300     -      Glu Leu Gly Gly Lys Phe Leu Ala - # Thr Asp Asn Arg Val Phe Gly     Val     #    320     -      Phe Ser Ala Lys Glu Thr Glu Glu - # Thr Lys Lys Glu Ala Leu Ser     Lys     #   335     -      Glu Thr Leu Ile Asp Gly Lys Leu - # Ile Thr Phe Ser Thr Lys Lys     Thr     #                350     -      Asp Ala Lys Thr Asn Ala Thr Thr - # Ser Thr Ala Ala Asn Thr Thr     Thr     #            365     -      Asp Thr Thr Ala Asn Thr Ile Thr - # Asp Glu Lys Asn Phe Lys Thr     Glu     #        380     -      Asp Ile Ser Ser Phe Gly Glu Ala - # Asp Tyr Leu Leu Ile Asp Lys     Tyr     #    400     -      Pro Ile Pro Leu Leu Pro Asp Lys - # Asn Thr Asn Asp Phe Ile Ser     Ser     #   415     -      Lys His His Thr Val Gly Asn Lys - # Arg Tyr Lys Val Glu Ala Cys     Cys     #                430     -      Ser Asn Leu Ser Tyr Val Lys Phe - # Gly Met Tyr Tyr Glu Asp Pro     Leu     #            445     -      Lys Glu Lys Glu Thr Glu Thr Glu - # Thr Glu Thr Glu Lys Asp Lys     Glu     #        460     -      Lys Glu Lys Glu Lys Asp Lys Asp - # Lys Glu Lys Gln Thr Ala Ala     Thr     #    480     -      Thr Asn Thr Tyr Tyr Gln Phe Leu - # Leu Gly His Arg Thr Pro Lys     Asp     #   495     -      Asp Ile Pro Lys Thr Gly Ser Ala - # Lys Tyr His Gly Ser Trp Phe     Gly     #                510     -      Tyr Ile Thr Asp Gly Lys Thr Ser - # Tyr Ser Pro Ser Gly Asp Lys     Lys     #            525     -      Arg Asp Lys Asn Ala Val Ala Glu - # Phe Asn Val Asp Phe Ala Glu     Lys     #        540     -      Lys Leu Thr Gly Glu Leu Lys Arg - # His Asp Thr Gly Asn Pro Val     Phe     #    560     -      Ser Ile Glu Ala Asn Phe Asn Asn - # Ser Ser Asn Ala Phe Thr Gly     Thr     #   575     -      Ala Thr Ala Thr Asn Phe Val Ile - # Asp Gly Lys Asn Ser Gln Asn     Lys     #                590     -      Asn Thr Pro Ile Asn Ile Thr Thr - # Lys Val Asn Gly Ala Phe Tyr     Gly     #            605     -      Pro Lys Ala Ser Glu Leu Gly Gly - # Tyr Phe Thr Tyr Asn Gly Asn     Ser     #        620     -      Thr Ala Thr Asn Ser Glu Ser Ser - # Ser Thr Val Ser Ser Ser Ser     Asn     #    640     -      Ser Lys Asn Ala Arg Ala Ala Val - # Val Phe Gly Ala Arg Gln Gln     Val     #   655     -      Glu Thr Thr Lys                      660     - (2) INFORMATION FOR SEQ ID NO:11:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 914 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:11:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys Leu     Leu     #   15     -      Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp Thr     Lys     #                 30     -      Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp Ser     Glu     #             45     -      Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Ile Arg Asp Arg Lys     Asp     #         60     -      Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu Ser     Ile     #     80     -      Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr Asp     Pro     #   95     -      Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly Tyr     Ser     #                110     -      Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp Gly     Leu     #            125     -      Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala Arg     Ser     #        140     -      Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu Asn     Val     #    160     -      Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr Gly     Asn     #   175     -      Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala Ala     Asp     #                190     -      Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn Ala     Tyr     #            205     -      Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala Gly     Lys     #        220     -      Gln Gly Gly Phe Asp Gly Val Ala - # Ile Tyr Thr Gln Arg Asn Ser     Ile     #    240     -      Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser Tyr     His     #   255     -      Arg Leu Ile Ala Lys Pro Glu Asp - # Gln Ser Ala Tyr Phe Val Met     Gln     #                270     -      Asp Glu Cys Pro Lys Pro Asp Asp - # Tyr Asn Ser Cys Leu Pro Phe     Ala     #            285     -      Lys Arg Pro Ala Ile Leu Ser Ser - # Gln Arg Glu Thr Val Ser Val     Ser     #        300     -      Asp Tyr Thr Gly Ala Asn Arg Ile - # Lys Pro Asn Pro Met Lys Tyr     Glu     #    320     -      Ser Gln Ser Trp Phe Leu Arg Gly - # Gly Tyr His Phe Ser Glu Gln     His     #   335     -      Tyr Ile Gly Gly Ile Phe Glu Phe - # Thr Gln Gln Lys Phe Asp Ile     Arg     #                350     -      Asp Met Thr Phe Pro Ala Tyr Leu - # Arg Ser Thr Glu Lys Arg Asp     Asp     #            365     -      Ser Ser Gly Ser Phe Tyr Pro Lys - # Gln Asp Tyr Gly Ala Tyr Gln     Arg     #        380     -      Ile Glu Asp Gly Arg Gly Val Asn - # Tyr Ala Ser Gly Leu Tyr Phe     Asp     #    400     -      Glu His His Arg Lys Gln Arg Val - # Gly Ile Glu Tyr Ile Tyr Glu     Asn     #   415     -      Lys Asn Lys Ala Gly Ile Ile Asp - # Lys Ala Val Leu Ser Ala Asn     Gln     #                430     -      Gln Asn Ile Ile Leu Asp Ser Tyr - # Met Gln His Thr His Cys Ser     Leu     #            445     -      Tyr Pro Asn Pro Ser Lys Asn Cys - # Arg Pro Thr Arg Asp Lys Pro     Tyr     #        460     -      Ser Tyr Tyr His Ser Asp Arg Asn - # Val Tyr Lys Glu Lys His Asn     Met     #    480     -      Leu Gln Leu Asn Leu Glu Lys Lys - # Ile Gln Gln Asn Trp Leu Thr     His     #   495     -      Gln Ile Val Phe Asn Leu Gly Phe - # Asp Asp Phe Thr Ser Ala Leu     Gln     #                510     -      His Lys Asp Tyr Leu Thr Arg Arg - # Val Thr Ala Thr Ala Lys Ser     Ile     #            525     -      Ser Glu Lys Ala Asn Glu Thr Arg - # Arg Asn Gly Tyr Lys Lys Gln     Pro     #        540     -      Tyr Leu Tyr Pro Lys Pro Thr Val - # Gly Phe Val Val Gln Asp His     Cys     #    560     -      Asp Tyr Lys Gly Asn Ser Ser Asn - # Tyr Arg Asp Cys Lys Val Arg     Leu     #   575     -      Ile Lys Gly Lys Asn Tyr Tyr Phe - # Ala Ala Arg Asn Asn Met Ala     Leu     #                590     -      Gly Lys Tyr Val Asp Leu Gly Leu - # Gly Ile Arg Tyr Asp Val Ser     Arg     #            605     -      Thr Lys Ala Asn Glu Ser Thr Ile - # Ser Val Gly Lys Phe Lys Asn     Phe     #        620     -      Ser Trp Asn Thr Gly Ile Val Ile - # Lys Pro Thr Glu Trp Leu Asp     Leu     #    640     -      Ser Tyr Arg Leu Ser Thr Gly Phe - # Arg Asn Pro Ser Phe Ala Glu     Met     #   655     -      Tyr Gly Trp Arg Tyr Gly Gly Asn - # Asn Ser Glu Val Tyr Val Gly     Lys     #                670     -      Phe Lys Pro Glu Thr Ser Arg Asn - # Gln Glu Phe Gly Leu Ala Leu     Lys     #            685     -      Gly Asp Phe Gly Asn Ile Glu Ile - # Ser His Phe Ser Asn Ala Tyr     Arg     #        700     -      Asn Leu Ile Ala Phe Ala Glu Glu - # Leu Asn Lys Asn Gly Thr Gly     Lys     #    720     -      Ala Asn Tyr Gly Tyr His Asn Ala - # Gln Asn Ala Lys Leu Val Gly     Val     #   735     -      Asn Ile Thr Ala Gln Leu Asp Phe - # Asn Gly Leu Trp Lys Arg Ile     Pro     #                750     -      Tyr Gly Trp Tyr Ala Thr Phe Ala - # Tyr Asn Arg Val Lys Val Lys     Asp     #            765     -      Gln Lys Ile Asn Ala Gly Leu Ala - # Ser Val Ser Ser Tyr Leu Phe     Asp     #        780     -      Ala Ile Gln Pro Ser Arg Tyr Ile - # Ile Gly Leu Gly Tyr Asp His     Pro     #    800     -      Ser Asn Thr Trp Gly Ile Asn Thr - # Met Phe Thr Gln Ser Lys Ala     Lys     #   815     -      Ser Gln Asn Glu Leu Leu Gly Lys - # Arg Ala Leu Gly Asn Asn Ser     Arg     #                830     -      Asp Val Lys Ser Thr Arg Lys Leu - # Thr Arg Ala Trp His Ile Leu     Asp     #            845     -      Val Ser Gly Tyr Tyr Met Ala Asn - # Lys Asn Ile Met Leu Arg Leu     Gly     #        860     -      Ile Tyr Asn Leu Phe Asn Tyr Arg - # Tyr Val Thr Trp Glu Ala Val     Arg     #    880     -      Gln Thr Ala Gln Gly Ala Val Asn - # Gln His Gln Asn Val Gly Ser     Tyr     #   895     -      Thr Arg Tyr Ala Ala Ser Gly Arg - # Asn Tyr Thr Leu Thr Leu Glu     Met     #                910     -      Lys Phe     - (2) INFORMATION FOR SEQ ID NO:12:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 654 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:12:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Thr - # Gly Gly Leu Ser Phe Leu Leu     Ser     #   15     -      Ala Cys Ser Gly Gly Gly Gly Ser - # Phe Asp Val Asp Asp Val Ser     Asn     #                 30     -      Pro Ser Ser Ser Lys Pro Arg Tyr - # Gln Asp Asp Thr Ser Asn Gln     Arg     #             45     -      Thr Lys Ser Asp Leu Glu Lys Leu - # Phe Ile Pro Ser Leu Gly Gly     Gly     #         60     -      Met Lys Leu Val Ala Gln Asn Phe - # Ile Gly Ala Arg Glu Pro Ser     Phe     #     80     -      Leu Asn Glu Asp Gly Tyr Met Ile - # Phe Ser Ser Leu Ser Thr Ile     Glu     #   95     -      Glu Asp Val Glu Lys Val Lys Asn - # Asn Asn Lys Asn Gly Gly Arg     Leu     #                110     -      Ile Gly Ser Ile Glu Glu Pro Asn - # Gly Thr Ser Gln Asn Ser Asn     Ser     #            125     -      Gln Glu Tyr Val Tyr Ser Gly Leu - # Tyr Tyr Ile Asp Ser Trp Arg     Asp     #        140     -      Tyr Lys Lys Glu Glu Gln Lys Ala - # Tyr Thr Gly Tyr Tyr Gly Tyr     Ala     #    160     -      Phe Tyr Tyr Gly Asn Glu Thr Ala - # Lys Asn Leu Pro Val Lys Gly     Val     #   175     -      Ala Lys Tyr Lys Gly Thr Trp Asn - # Phe Ile Thr Ala Thr Glu Asn     Gly     #                190     -      Lys Arg Tyr Ser Leu Phe Ser Asn - # Ser Ile Gly Gln Ala Tyr Ser     Arg     #            205     -      Arg Ser Ala Ile Ser Glu Asp Ile - # Tyr Asn Leu Glu Asn Gly Asp     Ala     #        220     -      Gly Leu Ile Ser Glu Phe Ser Val - # Asp Phe Gly Lys Lys Glu Leu     Thr     #    240     -      Gly Glu Leu Tyr Tyr Asn Glu Arg - # Lys Thr Ser Val Asn Glu Ser     Gln     #   255     -      Asn Thr Thr His Lys Leu Tyr Thr - # Leu Glu Ala Lys Val Tyr Ser     Asn     #                270     -      Arg Phe Arg Gly Lys Val Lys Pro - # Thr Lys Thr Lys Ser Glu Asp     His     #            285     -      Pro Phe Thr Ser Glu Gly Thr Leu - # Glu Gly Gly Phe Tyr Gly Pro     Asn     #        300     -      Ala Glu Glu Leu Gly Gly Lys Phe - # Leu Ala Asn Asp Glu Lys Val     Phe     #    320     -      Gly Val Phe Ser Ala Lys Glu Asp - # Pro Gln Asn Pro Glu Asn Gln     Lys     #   335     -      Leu Ser Thr Glu Thr Leu Ile Asp - # Gly Lys Leu Ile Thr Phe Lys     Arg     #                350     -      Thr Asp Ala Thr Thr Asn Ala Thr - # Thr Asp Ala Lys Thr Ser Ala     Thr     #            365     -      Thr Asp Ala Thr Ser Thr Thr Ala - # Asn Lys Lys Thr Asp Ala Glu     Asn     #        380     -      Phe Lys Thr Glu Asp Ile Pro Ser - # Phe Gly Glu Ala Asp Tyr Leu     Leu     #    400     -      Ile Gly Asn Gln Pro Ile Pro Leu - # Leu Pro Glu Lys Asn Thr Asp     Asp     #   415     -      Phe Ile Ser Ser Lys His His Thr - # Val Gly Gly Lys Thr Tyr Lys     Val     #                430     -      Glu Ala Cys Cys Lys Asn Leu Ser - # Tyr Val Lys Phe Gly Met Tyr     Tyr     #            445     -      Glu Asp Lys Asp Lys Asp Asn Lys - # Asn Glu Thr Asp Lys Glu Lys     Gly     #        460     -      Lys Glu Lys Pro Thr Thr Thr Thr - # Ser Ile Asn Thr Tyr Tyr Gln     Phe     #    480     -      Leu Leu Gly Leu Arg Thr Pro Lys - # Asp Glu Ile Pro Lys Glu Gly     Ser     #   495     -      Ala Lys Tyr His Gly Asn Trp Phe - # Gly Tyr Ile Ser Asp Gly Glu     Thr     #                510     -      Ser Tyr Ser Ala Ser Gly Asp Lys - # Glu Arg Ser Lys Asn Ala Val     Ala     #            525     -      Glu Phe Asp Val Ser Phe Ala Asn - # Lys Thr Leu Thr Gly Glu Leu     Lys     #        540     -      Arg His Asp Asn Gly Asn Thr Val - # Phe Lys Ile Asn Ala Glu Leu     Asn     #    560     -      Gly Ser Asn Asp Phe Thr Gly Thr - # Ala Thr Ala Thr Asn Phe Val     Ile     #   575     -      Asp Gly Asn Asn Ser Gln Thr Ser - # Asn Ala Lys Ile Asn Ile Thr     Thr     #                590     -      Lys Val Asn Gly Ala Phe Tyr Gly - # Pro Lys Ala Ser Glu Leu Gly     Gly     #            605     -      Tyr Phe Thr Tyr Asn Gly Lys Asn - # Pro Thr Ala Thr Asn Ser Glu     Ser     #        620     -      Ser Ser Thr Val Pro Ser Pro Pro - # Asn Ser Pro Asn Ala Ser Ala     Ala     #    640     -      Val Val Phe Gly Ala Lys Lys Gln - # Val Glu Thr Thr Asn Lys     #   650     - (2) INFORMATION FOR SEQ ID NO:13:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:13:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ala Glu Thr Gln Ser Ile Lys Asp - # Thr Lys Glu Ala Ile Ser Ser     Glu     #   15     -      Val Asp Thr Gln Ser Thr Glu Asp - # Ser Glu Leu Glu Thr Ile Ser     Val     #                 30     -      Thr Ala Glu Lys                  35     - (2) INFORMATION FOR SEQ ID NO:14:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:14:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ser Val Thr Ala Glu Lys Val Arg - # Asp Arg Lys Asp Asn Glu Val     Thr     #   15     -      Gly Leu Gly Lys Ile Ile Lys Thr - # Ser Glu Ser Ile Ser Arg Glu     Gln     #                 30     -      Val Leu Asn Ile                  35     - (2) INFORMATION FOR SEQ ID NO:15:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:15:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr Asp     Pro     #   15     -      Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly Tyr     Ser     #                 30     -      Ile Arg Gly Met                  35     - (2) INFORMATION FOR SEQ ID NO:16:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:16:(xi) SEQUENCE DESCRIPTION: SEQ     -      Gly Tyr Ser Ile Arg Gly Met Asp - # Arg Asn Arg Val Ala Leu Leu     Val     #   15     -      Asp Gly Leu Pro Gln Thr Gln Ser - # Tyr Val Val Gln Ser Pro Leu     Val     #                 30     -      Ala Arg Ser Gly                  35     - (2) INFORMATION FOR SEQ ID NO:17:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:17:(xi) SEQUENCE DESCRIPTION: SEQ     -      Pro Leu Val Ala Arg Ser Gly Tyr - # Gly Thr Gly Ala Ile Asn Glu     Ile     #   15     -      Glu Tyr Glu Asn Val Lys Ala Val - # Glu Ile Ser Lys Gly Gly Ser     Ser     #                 30     -      Ser Glu Tyr Gly                  35     - (2) INFORMATION FOR SEQ ID NO:18:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:18:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ser Ser Ser Glu Tyr Gly Asn Gly - # Ala Leu Ala Gly Ser Val Thr     Phe     #   15     -      Gln Ser Lys Ser Ala Ala Asp Ile - # Leu Glu Gly Asp Lys Ser Trp     Gly     #                 30     -      Ile Gln Thr Lys                  35     - (2) INFORMATION FOR SEQ ID NO:19:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:19:(xi) SEQUENCE DESCRIPTION: SEQ     -      Gly Ile Gln Thr Lys Asn Ala Tyr - # Ser Ser Lys Asn Lys Gly Phe     Thr     #   15     -      His Ser Leu Ala Val Ala Gly Lys - # Gln Gly Gly Phe Glu Gly Val     Ala     #                 30     -      Ile Tyr Thr His                  35     - (2) INFORMATION FOR SEQ ID NO:20:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:20:(xi) SEQUENCE DESCRIPTION: SEQ     -      Gly Val Ala Ile Tyr Thr His Arg - # Asn Ser Ile Glu Thr Gln Val     His     #   15     -      Lys Asp Ala Leu Lys Gly Val Gln - # Ser Tyr Asp Arg Phe Ile Ala     Thr     #                 30     -      Thr Glu Asp Gln                  35     - (2) INFORMATION FOR SEQ ID NO:21:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:21:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ile Ala Thr Thr Glu Asp Gln Ser - # Ala Tyr Phe Val Met Gln Asp     Glu     #   15     -      Cys Leu Asp Gly Tyr Asp Lys Cys - # Lys Thr Ser Pro Lys Arg Pro     Ala     #                 30     -      Thr Leu Ser Thr                  35     - (2) INFORMATION FOR SEQ ID NO:22:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:22:(xi) SEQUENCE DESCRIPTION: SEQ     -      Pro Ala Thr Leu Ser Thr Gln Arg - # Glu Thr Val Ser Val Ser Asp     Tyr     #   15     -      Thr Gly Ala Asn Arg Ile Lys Pro - # Asn Pro Met Lys Tyr Glu Ser     Gln     #                 30     -      Ser Trp Phe Leu                  35     - (2) INFORMATION FOR SEQ ID NO:23:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:23:(xi) SEQUENCE DESCRIPTION: SEQ     -      Tyr Glu Ser Gln Ser Trp Phe Leu - # Arg Gly Gly Tyr His Phe Ser     Glu     #   15     -      Gln His Tyr Ile Gly Gly Ile Phe - # Glu Phe Thr Gln Gln Lys Phe     Asp     #                 30     -      Ile Arg Asp Met                  35     - (2) INFORMATION FOR SEQ ID NO:24:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:24:(xi) SEQUENCE DESCRIPTION: SEQ     -      Lys Phe Asp Ile Arg Asp Met Thr - # Phe Pro Ala Tyr Leu Arg Pro     Thr     #   15     -      Glu Asp Lys Asp Leu Gln Ser Arg - # Pro Phe Tyr Pro Lys Gln Asp     Tyr     #                 30     -      Gly Ala Tyr Gln                  35     - (2) INFORMATION FOR SEQ ID NO:25:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:25:(xi) SEQUENCE DESCRIPTION: SEQ     -      Asp Tyr Gly Ala Tyr Gln His Ile - # Gly Asp Gly Arg Gly Val Lys     Tyr     #   15     -      Ala Ser Gly Leu Tyr Phe Asp Glu - # His His Arg Lys Gln Arg Val     Gly     #                 30     -      Ile Glu Tyr Ile                  35     - (2) INFORMATION FOR SEQ ID NO:26:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:26:(xi) SEQUENCE DESCRIPTION: SEQ     -      Gly Ile Glu Tyr Ile Tyr Glu Asn - # Lys Asn Lys Ala Gly Ile Ile     Asp     #   15     -      Lys Ala Val Leu Ser Ala Asn Gln - # Gln Asn Ile Ile Leu Asp Ser     Tyr     #                 30     -      Met Arg His Thr                  35     - (2) INFORMATION FOR SEQ ID NO:27:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:27:(xi) SEQUENCE DESCRIPTION: SEQ     -      Asp Ser Tyr Met Arg His Thr His - # Cys Ser Leu Tyr Pro Asn Pro     Ser     #   15     -      Lys Asn Cys Arg Pro Thr Leu Asp - # Lys Pro Tyr Ser Tyr Tyr His     Ser     #                 30     -      Asp Arg Asn Val                  35     - (2) INFORMATION FOR SEQ ID NO:28:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:28:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ser Asp Arg Asn Val Tyr Lys Glu - # Lys His Asn Met Leu Gln Leu     Asn     #   15     -      Leu Glu Lys Lys Ile Gln Gln Asn - # Trp Leu Thr His Gln Ile Ala     Phe     #                 30     -      Asn Leu Gly Phe                  35     - (2) INFORMATION FOR SEQ ID NO:29:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:29:(xi) SEQUENCE DESCRIPTION: SEQ     -      Thr His Gln Ile Ala Phe Asn Leu - # Gly Phe Asp Asp Phe Thr Ser     Ala     #   15     -      Leu Gln His Lys Asp Tyr Leu Thr - # Arg Arg Val Ile Ala Thr Ala     Ser     #                 30     -      Ser Ile Ser Glu                  35     - (2) INFORMATION FOR SEQ ID NO:30:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 37 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:30:(xi) SEQUENCE DESCRIPTION: SEQ     -      Thr Ala Ser Ser Ile Ser Glu Lys - # Arg Gly Glu Ala Arg Arg Asn     Gly     #   15     -      Leu Gln Ser Ser Pro Tyr Leu Tyr - # Pro Thr Pro Lys Ala Glu Leu     Val     #                 30     -      Gly Gly Asp Leu Cys                  35     - (2) INFORMATION FOR SEQ ID NO:31:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:31:(xi) SEQUENCE DESCRIPTION: SEQ     -      Leu Val Gly Gly Asp Leu Cys Asn - # Tyr Gln Gly Lys Ser Ser Asn     Tyr     #   15     -      Ser Asp Cys Lys Val Arg Leu Ile - # Lys Gly Lys Asn Tyr Tyr Phe     Ala     #                 30     -      Ala Arg Asn Asn                  35     - (2) INFORMATION FOR SEQ ID NO:32:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:32:(xi) SEQUENCE DESCRIPTION: SEQ     -      Phe Ala Ala Arg Asn Asn Met Ala - # Leu Gly Lys Tyr Val Asp Leu     Gly     #   15     -      Leu Gly Met Arg Tyr Asp Val Ser - # Arg Thr Lys Ala Asn Glu Ser     Thr     #                 30     -      Ile Ser Val Gly                  35     - (2) INFORMATION FOR SEQ ID NO:33:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:33:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ser Thr Ile Ser Val Gly Lys Phe - # Lys Asn Phe Ser Trp Asn Thr     Gly     #   15     -      Ile Val Ile Lys Pro Thr Glu Trp - # Leu Asp Leu Ser Tyr Arg Leu     Ser     #                 30     -      Thr Gly Phe Arg                  35     - (2) INFORMATION FOR SEQ ID NO:34:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:34:(xi) SEQUENCE DESCRIPTION: SEQ     -      Leu Ser Thr Gly Phe Arg Asn Pro - # Ser Phe Ala Glu Met Tyr Gly     Trp     #   15     -      Arg Tyr Gly Gly Lys Asp Thr Asp - # Val Tyr Ile Gly Lys Phe Lys     Pro     #                 30     -      Glu Thr Ser Arg                  35     - (2) INFORMATION FOR SEQ ID NO:35:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:35:(xi) SEQUENCE DESCRIPTION: SEQ     -      Lys Pro Glu Thr Ser Arg Asn Gln - # Glu Phe Gly Leu Ala Leu Lys     Gly     #   15     -      Asp Phe Gly Asn Ile Glu Ile Ser - # His Phe Ser Asn Ala Tyr Arg     Asn     #                 30     -      Leu Ile Ala Phe                  35     - (2) INFORMATION FOR SEQ ID NO:36:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:36:(xi) SEQUENCE DESCRIPTION: SEQ     -      Tyr Arg Asn Leu Ile Ala Phe Ala - # Glu Glu Leu Ser Lys Asn Gly     Thr     #   15     -      Thr Gly Lys Gly Asn Tyr Gly Tyr - # His Asn Ala Gln Asn Ala Lys     Leu     #                 30     -      Val Gly Val Asn                  35     - (2) INFORMATION FOR SEQ ID NO:37:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:37:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ala Lys Leu Val Gly Val Asn Ile - # Thr Ala Gln Leu Asp Phe Asn     Gly     #   15     -      Leu Trp Lys Arg Ile Pro Tyr Gly - # Trp Tyr Ala Thr Phe Ala Tyr     Asn     #                 30     -      Arg Val Lys Val                  35     - (2) INFORMATION FOR SEQ ID NO:38:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:38:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ala Tyr Asn Arg Val Lys Val Lys - # Asp Gln Lys Ile Asn Ala Gly     Leu     #   15     -      Ala Ser Val Ser Ser Tyr Leu Phe - # Asp Ala Ile Gln Pro Ser Arg     Tyr     #                 30     -      Ile Ile Gly Leu                  35     - (2) INFORMATION FOR SEQ ID NO:39:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:39:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ser Arg Tyr Ile Ile Gly Leu Asp - # Tyr Asp His Pro Ser Asn Thr     Trp     #   15     -      Gly Ile Lys Thr Met Phe Thr Gln - # Ser Lys Ala Lys Ser Gln Asn     Glu     #                 30     -      Leu Leu Gly Lys                  35     - (2) INFORMATION FOR SEQ ID NO:40:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:40:(xi) SEQUENCE DESCRIPTION: SEQ     -      Asn Glu Leu Leu Gly Lys Arg Ala - # Leu Gly Asn Asn Ser Arg Asn     Val     #   15     -      Lys Ser Thr Arg Lys Leu Thr Arg - # Ala Trp His Ile Leu Asp Val     Ser     #                 30     -      Gly Tyr Tyr Met                  35     - (2) INFORMATION FOR SEQ ID NO:41:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 30 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:41:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ser Gly Tyr Tyr Met Val Asn Arg - # Ser Ile Leu Phe Arg Leu Gly     Val     #   15     -      Tyr Asn Leu Leu Asn Tyr Arg Tyr - # Val Thr Trp Glu Ala Val     #                 30     - (2) INFORMATION FOR SEQ ID NO:42:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 23 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:42:(xi) SEQUENCE DESCRIPTION: SEQ     -      Leu Leu Asn Tyr Arg Tyr Val Thr - # Trp Glu Ala Val Arg Gln Thr     Ala     #   15     -      Gln Gly Ala Glu Phe Asp Ile                      20     - (2) INFORMATION FOR SEQ ID NO:43:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 9 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:43:(xi) SEQUENCE DESCRIPTION: SEQ     -      Asp Asn Glu Val Thr Gly Leu Gly - # Lys     #  5 1     - (2) INFORMATION FOR SEQ ID NO:44:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 16 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:44:(xi) SEQUENCE DESCRIPTION: SEQ     -      Glu Gln Val Leu Asn Ile Arg Asp - # Leu Thr Arg Tyr Asp Pro Gly     Ile     #   15     - (2) INFORMATION FOR SEQ ID NO:45:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:45:(xi) SEQUENCE DESCRIPTION: SEQ     -      Glu Gln Val Leu Asn Ile Arg Asp - # Leu Thr Arg Tyr Asp Pro Gly     Ile     #   15     -      Ser Val Val Glu Gln Gly Arg Gly - # Ala Ser Ser Gly Tyr Ser Ile     Arg     #                 30     -      Gly Met Asp                  35     - (2) INFORMATION FOR SEQ ID NO:46:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 19 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:46:(xi) SEQUENCE DESCRIPTION: SEQ     -      Gly Ala Ile Asn Glu Ile Glu Tyr - # Glu Asn Val Lys Ala Val Glu     Ile     #   15     -      Ser Lys Gly     - (2) INFORMATION FOR SEQ ID NO:47:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 7 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:47:(xi) SEQUENCE DESCRIPTION: SEQ     -      Gly Ala Leu Ala Gly Ser Val     #  5 1     - (2) INFORMATION FOR SEQ ID NO:48:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 15 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:48:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ala Glu Thr Gln Ser Ile Lys Asp - # Thr Lys Glu Ala Ile Ser Cys     #   15     - (2) INFORMATION FOR SEQ ID NO:49:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 14 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:49:(xi) SEQUENCE DESCRIPTION: SEQ     -      Cys Ser Gly Gly Gly Ser Phe Asp - # Val Asp Asn Val Ser Asn     #   10     - (2) INFORMATION FOR SEQ ID NO:50:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 31 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:50:(xi) SEQUENCE DESCRIPTION: SEQ     -      Leu Glu Gly Gly Phe Tyr Gly Pro - # Lys Gly Glu Glu Leu Gly Phe     Arg     #   15     -      Phe Leu Ala Gly Asp Lys Lys Val - # Phe Gly Val Phe Ser Ala Lys     #                 30     - (2) INFORMATION FOR SEQ ID NO:51:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 23 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:51:(xi) SEQUENCE DESCRIPTION: SEQ     -      Thr Val Gly Lys Lys Thr Tyr Gln - # Val Glu Ala Cys Cys Ser Asn     Leu     #   15     -      Ser Tyr Val Lys Phe Gly Met                      20     - (2) INFORMATION FOR SEQ ID NO:52:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 23 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:52:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ala Thr Val Lys Gly Ala Phe Tyr - # Gly Pro Lys Ala Ser Glu Leu     Gly     #   15     -      Gly Tyr Phe Thr Tyr Asn Gly                      20     - (2) INFORMATION FOR SEQ ID NO:53:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:53:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Leu Ala Ala Leu Asn Leu - # Phe Asp Arg Asn Lys Pro Ser     Leu     #   15     -      Leu Asn Glu Asp Ser Tyr Met Ile - # Phe Ser Ser Arg Ser Thr Ile     Glu     #                 30     -      Glu Asp Val                  35     - (2) INFORMATION FOR SEQ ID NO:54:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:54:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ser Thr Ile Glu Glu Asp Val Lys - # Asn Asp Asn Gln Asn Gly Glu     His     #   15     -      Pro Ile Asp Ser Ile Val Asp Pro - # Arg Ala Pro Asn Ser Asn Glu     Asn     #                 30     -      Arg His Gly                  35     - (2) INFORMATION FOR SEQ ID NO:55:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:55:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ser Asn Glu Asn Arg His Gly Gln - # Lys Tyr Val Tyr Ser Gly Leu     Tyr     #   15     -      Tyr Ile Gln Ser Trp Ser Leu Arg - # Asp Leu Pro Asn Lys Lys Phe     Tyr     #                 30     -      Ser Gly Tyr                  35     - (2) INFORMATION FOR SEQ ID NO:56:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:56:(xi) SEQUENCE DESCRIPTION: SEQ     -      Lys Lys Phe Tyr Ser Gly Tyr Tyr - # Gly Tyr Ala Tyr Tyr Phe Gly     Asn     #   15     -      Thr Thr Ala Ser Ala Leu Pro Val - # Gly Gly Val Ala Thr Tyr Lys     Gly     #                 30     -      Thr Trp Ser                  35     - (2) INFORMATION FOR SEQ ID NO:57:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:57:(xi) SEQUENCE DESCRIPTION: SEQ     -      Thr Tyr Lys Gly Thr Trp Ser Phe - # Ile Thr Ala Ala Glu Asn Gly     Lys     #   15     -      Asn Tyr Glu Leu Leu Arg Asn Ser - # Gly Gly Gly Gln Ala Tyr Ser     Arg     #                 30     -      Arg Ser Ala                  35     - (2) INFORMATION FOR SEQ ID NO:58:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:58:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ala Tyr Ser Arg Arg Ser Ala Thr - # Pro Glu Asp Ile Asp Leu Asp     Arg     #   15     -      Lys Thr Gly Leu Thr Ser Glu Phe - # Thr Val Asn Phe Gly Thr Lys     Lys     #                 30     -      Leu Thr Gly                  35     - (2) INFORMATION FOR SEQ ID NO:59:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:59:(xi) SEQUENCE DESCRIPTION: SEQ     -      Gly Thr Lys Lys Leu Thr Gly Gly - # Leu Tyr Tyr Asn Leu Arg Glu     Thr     #   15     -      Asp Ala Asn Lys Ser Gln Asn Arg - # Thr His Lys Leu Tyr Asp Leu     Glu     #                 30     -      Ala Asp Val                  35     - (2) INFORMATION FOR SEQ ID NO:60:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:60:(xi) SEQUENCE DESCRIPTION: SEQ     -      Tyr Asp Leu Glu Ala Asp Val His - # Ser Asn Arg Phe Arg Gly Lys     Val     #   15     -      Lys Pro Thr Lys Lys Glu Ser Ser - # Glu Glu His Pro Phe Thr Ser     Glu     #                 30     -      Gly Thr Leu                  35     - (2) INFORMATION FOR SEQ ID NO:61:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:61:(xi) SEQUENCE DESCRIPTION: SEQ     -      Phe Thr Ser Glu Gly Thr Leu Glu - # Gly Gly Phe Tyr Gly Pro Glu     Gly     #   15     -      Gln Glu Leu Gly Gly Lys Phe Leu - # Ala His Asp Lys Lys Val Leu     Gly     #                 30     -      Val Phe Ser                  35     - (2) INFORMATION FOR SEQ ID NO:62:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:62:(xi) SEQUENCE DESCRIPTION: SEQ     -      Lys Val Leu Gly Val Phe Ser Ala - # Lys Glu Gln Gln Glu Thr Ser     Glu     #   15     -      Asn Lys Lys Leu Pro Lys Glu Thr - # Leu Ile Asp Gly Lys Leu Thr     Thr     #                 30     -      Phe Lys Thr                  35     - (2) INFORMATION FOR SEQ ID NO:63:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:63:(xi) SEQUENCE DESCRIPTION: SEQ     -      Lys Leu Thr Thr Phe Lys Thr Thr - # Asn Ala Thr Ala Asn Ala Thr     Thr     #   15     -      Asp Ala Thr Thr Ser Thr Thr Ala - # Ser Thr Lys Thr Asp Thr Thr     Thr     #                 30     -      Asn Ala Thr                  35     - (2) INFORMATION FOR SEQ ID NO:64:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:64:(xi) SEQUENCE DESCRIPTION: SEQ     -      Asp Thr Thr Thr Asn Ala Thr Ala - # Asn Thr Glu Asn Phe Thr Thr     Lys     #   15     -      Asp Ile Pro Ser Leu Gly Glu Ala - # Asp Tyr Leu Leu Ile Asp Asn     Tyr     #                 30     -      Pro Val Pro                  35     - (2) INFORMATION FOR SEQ ID NO:65:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:65:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ile Asp Asn Tyr Pro Val Pro Leu - # Phe Pro Glu Ser Gly Asp Phe     Ile     #   15     -      Ser Ser Lys His His Thr Val Gly - # Lys Lys Thr Tyr Gln Val Glu     Ala     #                 30     -      Cys Cys Ser                  35     - (2) INFORMATION FOR SEQ ID NO:66:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 36 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:66:(xi) SEQUENCE DESCRIPTION: SEQ     -      Cys Ser Asn Leu Ser Tyr Val Lys - # Phe Gly Met Tyr Tyr Glu Ala     Pro     #   15     -      Pro Lys Glu Glu Glu Lys Glu Lys - # Glu Lys Asp Lys Asp Lys Glu     Lys     #                 30     -      Glu Lys Gln Ala                  35     - (2) INFORMATION FOR SEQ ID NO:67:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:67:(xi) SEQUENCE DESCRIPTION: SEQ     -      Lys Glu Lys Asp Lys Asp Lys Glu - # Lys Glu Lys Gln Ala Thr Thr     Ser     #   15     -      Ile Lys Thr Tyr Tyr Gln Phe Leu - # Leu Gly Leu Arg Thr Pro Ser     Ser     #                 30     -      Glu Ile Pro                  35     - (2) INFORMATION FOR SEQ ID NO:68:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:68:(xi) SEQUENCE DESCRIPTION: SEQ     -      Thr Pro Ser Ser Glu Ile Pro Lys - # Glu Gly Ser Ala Lys Tyr His     Gly     #   15     -      Asn Trp Phe Gly Tyr Ile Ser Asp - # Gly Glu Thr Ser Tyr Ser Ala     Ser     #                 30     -      Gly Asp Lys                  35     - (2) INFORMATION FOR SEQ ID NO:69:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:69:(xi) SEQUENCE DESCRIPTION: SEQ     -      Tyr Ser Ala Ser Gly Asp Lys Glu - # Arg Ser Lys Asn Ala Val Ala     Glu     #   15     -      Phe Asn Val Asn Phe Ala Glu Lys - # Thr Leu Thr Gly Glu Leu Lys     Arg     #                 30     -      His Asp Thr                  35     - (2) INFORMATION FOR SEQ ID NO:70:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:70:(xi) SEQUENCE DESCRIPTION: SEQ     -      Glu Leu Lys Arg His Asp Thr Gln - # Asn Pro Val Phe Lys Ile Asn     Ala     #   15     -      Thr Phe Gln Ser Gly Lys Asn Asp - # Phe Thr Gly Thr Ala Thr Ala     Lys     #                 30     -      Asp Leu Ala                  35     - (2) INFORMATION FOR SEQ ID NO:71:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 35 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:71:(xi) SEQUENCE DESCRIPTION: SEQ     -      Ala Thr Ala Lys Asp Leu Ala Ile - # Asp Gly Lys Asn Thr Gln Gly     Thr     #   15     -      Ser Lys Val Asn Phe Thr Ala Thr - # Val Asn Gly Ala Phe Tyr Gly     Pro     #                 30     -      His Ala Thr                  35     - (2) INFORMATION FOR SEQ ID NO:72:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 26 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:72:(xi) SEQUENCE DESCRIPTION: SEQ     -      Phe Tyr Gly Pro His Ala Thr Glu - # Leu Gly Gly Tyr Phe Thr Tyr     Asn     #   15     -      Gly Asn Asn Pro Thr Asp Lys Asn - # Ser Ser     #                 25     - (2) INFORMATION FOR SEQ ID NO:73:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 31 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:73:(xi) SEQUENCE DESCRIPTION: SEQ     -      Cys Pro Thr Asp Lys Asn Ser Ser - # Ser Asn Ser Glu Lys Ala Arg     Ala     #   15     -      Ala Val Val Phe Gly Ala Lys Lys - # Gln Gln Val Glu Thr Thr Lys     #                 30     - (2) INFORMATION FOR SEQ ID NO:74:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 8 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:74:(xi) SEQUENCE DESCRIPTION: SEQ     -      Leu Glu Gly Gly Phe Tyr Gly Pro     #  5 1     - (2) INFORMATION FOR SEQ ID NO:75:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 8 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:75:(xi) SEQUENCE DESCRIPTION: SEQ     -      Cys Ser Gly Gly Gly Ser Phe Asp     #  5 1     - (2) INFORMATION FOR SEQ ID NO:76:     -      (i) SEQUENCE CHARACTERISTICS:     #acid     (A) LENGTH: 6 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:76:(xi) SEQUENCE DESCRIPTION: SEQ     -      Tyr Val Tyr Ser Gly Leu     #  5 1     - (2) INFORMATION FOR SEQ ID NO:77:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 11 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:77:(xi) SEQUENCE DESCRIPTION: SEQ     -      Cys Cys Ser Asn Leu Ser Tyr Val - # Lys Phe Gly     #   10     - (2) INFORMATION FOR SEQ ID NO:78:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 7 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:78:(xi) SEQUENCE DESCRIPTION: SEQ     -      Phe Leu Leu Gly His Arg Thr     #  5 1     - (2) INFORMATION FOR SEQ ID NO:79:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 6 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:79:(xi) SEQUENCE DESCRIPTION: SEQ     -      Glu Phe Asn Val Asp Phe     #  5 1     - (2) INFORMATION FOR SEQ ID NO:80:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 7 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:80:(xi) SEQUENCE DESCRIPTION: SEQ     -      Asn Ala Phe Thr Gly Thr Ala     #  5 1     - (2) INFORMATION FOR SEQ ID NO:81:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 7 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:81:(xi) SEQUENCE DESCRIPTION: SEQ     -      Val Asn Gly Ala Phe Tyr Gly     #  5 1     - (2) INFORMATION FOR SEQ ID NO:82:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 6 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:82:(xi) SEQUENCE DESCRIPTION: SEQ     -      Glu Leu Gly Gly Tyr Phe     #  5 1     - (2) INFORMATION FOR SEQ ID NO:83:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 6 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:83:(xi) SEQUENCE DESCRIPTION: SEQ     -      Val Val Phe Gly Ala Arg     #  5 1     - (2) INFORMATION FOR SEQ ID NO:84:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 6 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:84:(xi) SEQUENCE DESCRIPTION: SEQ     -      Val Val Phe Gly Ala Lys     #  5 1     - (2) INFORMATION FOR SEQ ID NO:85:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 7 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:85:(xi) SEQUENCE DESCRIPTION: SEQ     -      Leu Glu Gly Gly Phe Tyr Gly     #  5 1     - (2) INFORMATION FOR SEQ ID NO:86:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 103 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:86:(xi) SEQUENCE DESCRIPTION: SEQ     - TATGGAAACT CAAAGTATAA AAGATACAAA AGAAGCTATA TCATCTGAAG TG - #GACACTCA       60     #103               GAAT TAGAAACTAT CTCAGTCACT GCA     - (2) INFORMATION FOR SEQ ID NO:87:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 97 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:87:(xi) SEQUENCE DESCRIPTION: SEQ     - ACCTTTGAGT TTCATATTTT CTATGTTTTC TTCGATATAG TAGACTTCAC CT - #GTGAGTTT       60     #      97          TAAT CTTTGATAGA GTCAGTG     - (2) INFORMATION FOR SEQ ID NO:88:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 115 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:88:(xi) SEQUENCE DESCRIPTION: SEQ     - TATGAAAGCT ACTAAACTGG TTCTGGGTGC TGTTATCCTG GGTTCCACTC TG - #CTGGCTGG       60     - TTGTAGCGGA GGTGGTTGTT TTGATGTAGA TAACGTCTCT AATACCCCCT CT - #TCT      115     - (2) INFORMATION FOR SEQ ID NO:89:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 116 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:89:(xi) SEQUENCE DESCRIPTION: SEQ     - ACTTTCGATG ATTTGACCAA GACCCACGAC AATAGGACCC AAGGTGAGAC GA - #CCGACCAA       60     - CATCGCCTCC ACCAACAAAA CTACATCTAT TGCAGAGATT ATGGGGGAGA AG - #ATTT      116     - (2) INFORMATION FOR SEQ ID NO:90:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 109 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:90:(xi) SEQUENCE DESCRIPTION: SEQ     - TATGCGATAT CTGGCAACAT TGTTGTTATC TCTGGCGGTG TTAATCACCG CT - #GGTTGTAG       60     #              109TGATG TAGATAACGT CTCTAATACC CCCTCTTCT     - (2) INFORMATION FOR SEQ ID NO:91:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 110 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:91:(xi) SEQUENCE DESCRIPTION: SEQ     - ACGCTATAGA CCGTTGTAAC AACAATAGAG ACCGCCACAA TTAGTGGCGA CC - #AACATCGC       60     #             110CTACAT CTATTGCAGA GATTATGGGG GAGAAGATTT     - (2) INFORMATION FOR SEQ ID NO:92:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 117 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:92:(xi) SEQUENCE DESCRIPTION: SEQ     - TATGCAACTG AACAAAGTGC TGAAAGGGCT GATGATTGCT CTGCCTGTTA TG - #GCAATGCT       60     - GGTTGTAGCG GAGGTGGTTC TTTTGATGTA GATAACGTCT CTAATACCCC CT - #CTTCT      117     - (2) INFORMATION FOR SEQ ID NO:93:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 119 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:93:(xi) SEQUENCE DESCRIPTION: SEQ     - ACGTTGACTT GTTTCACGAC TTTCCCGACT ACTAACGAGA CGGACAATAC CG - #TTAACGAC       60     - CAACATCGCC TCCACCAAGA AAACTACATC TATTGCAGAG ATTATGGGGG AG - #AAGATTT      119     - (2) INFORMATION FOR SEQ ID NO:94:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 908 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:94:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met Gln Gln Gln His Leu Phe Arg - # Leu Asn Ile Leu Cys Leu Ser     Leu     #   15     -      Met Thr Ala Leu Pro Val Tyr Ala - # Glu Asn Val Gln Ala Glu Gln     Ala     #                 30     -      Gln Glu Lys Gln Leu Asp Thr Ile - # Gln Val Lys Ala Lys Lys Gln     Lys     #             45     -      Thr Arg Arg Asp Asn Glu Val Thr - # Gly Leu Gly Lys Leu Val Lys     Ser     #         60     -      Ser Asp Thr Leu Ser Lys Glu Gln - # Val Leu Asn Ile Arg Asp Leu     Thr     #     80     -      Arg Tyr Asp Pro Gly Ile Ala Val - # Val Glu Gln Gly Arg Gly Ala     Ser     #   95     -      Ser Gly Tyr Ser Ile Arg Gly Met - # Asp Lys Asn Arg Val Ser Leu     Thr     #                110     -      Val Asp Gly Val Ser Gln Ile Gln - # Ser Tyr Thr Ala Gln Ala Ala     Leu     #            125     -      Gly Gly Thr Arg Thr Ala Gly Ser - # Ser Gly Ala Ile Asn Glu Ile     Glu     #        140     -      Tyr Glu Asn Val Lys Ala Val Glu - # Ile Ser Lys Gly Ser Asn Ser     Ser     #    160     -      Glu Tyr Gly Asn Gly Ala Leu Ala - # Gly Ser Val Ala Phe Gln Thr     Lys     #   175     -      Thr Ala Ala Asp Ile Ile Gly Glu - # Gly Lys Gln Trp Gly Ile Gln     Ser     #                190     -      Lys Thr Ala Tyr Ser Gly Lys Asp - # His Ala Leu Thr Gln Ser Leu     Ala     #            205     -      Leu Ala Gly Arg Ser Gly Gly Ala - # Glu Ala Leu Leu Ile Tyr Thr     Lys     #        220     -      Arg Arg Gly Arg Glu Ile His Ala - # His Lys Asp Ala Gly Lys Gly     Val     #    240     -      Gln Ser Phe Asn Arg Leu Val Leu - # Asp Glu Asp Lys Lys Glu Gly     Gly     #   255     -      Ser Gln Tyr Arg Tyr Phe Ile Val - # Glu Glu Glu Cys His Asn Gly     Tyr     #                270     -      Ala Ala Cys Lys Asn Lys Leu Lys - # Glu Asp Ala Ser Val Lys Asp     Glu     #            285     -      Arg Lys Thr Val Ser Thr Gln Asp - # Tyr Thr Gly Ser Asn Arg Leu     Leu     #        300     -      Ala Asn Pro Leu Glu Tyr Gly Ser - # Gln Ser Trp Leu Phe Arg Pro     Gly     #    320     -      Trp His Leu Asp Asn Arg His Tyr - # Val Gly Ala Val Leu Glu Arg     Thr     #   335     -      Gln Gln Thr Phe Asp Thr Arg Asp - # Met Thr Val Pro Ala Tyr Phe     Thr     #                350     -      Ser Glu Asp Tyr Val Pro Gly Ser - # Leu Lys Gly Leu Gly Lys Tyr     Ser     #            365     -      Gly Asp Asn Lys Ala Glu Arg Leu - # Phe Val Gln Gly Glu Gly Ser     Thr     #        380     -      Leu Gln Gly Ile Gly Tyr Gly Thr - # Gly Val Phe Tyr Asp Glu Arg     His     #    400     -      Thr Lys Asn Arg Tyr Gly Val Glu - # Tyr Val Tyr His Asn Ala Asp     Lys     #   415     -      Asp Thr Trp Ala Asp Tyr Ala Arg - # Leu Ser Tyr Asp Arg Gln Gly     Ile     #                430     -      Asp Leu Asp Asn Arg Leu Gln Gln - # Thr His Cys Ser His Asp Gly     Ser     #            445     -      Asp Lys Asn Cys Arg Pro Asp Gly - # Asn Lys Pro Tyr Ser Phe Tyr     Lys     #        460     -      Ser Asp Arg Met Ile Tyr Glu Glu - # Ser Arg Asn Leu Phe Gln Ala     Val     #    480     -      Phe Lys Lys Ala Phe Asp Thr Ala - # Lys Ile Arg His Asn Leu Ser     Ile     #   495     -      Asn Leu Gly Tyr Asp Arg Phe Lys - # Ser Gln Leu Ser His Ser Asp     Tyr     #                510     -      Tyr Leu Gln Asn Ala Val Gln Ala - # Tyr Asp Leu Ile Thr Pro Lys     Lys     #            525     -      Pro Pro Phe Pro Asn Gly Ser Lys - # Asp Asn Pro Tyr Arg Val Ser     Ile     #        540     -      Gly Lys Thr Thr Val Asn Thr Ser - # Pro Ile Cys Arg Phe Gly Asn     Asn     #    560     -      Thr Tyr Thr Asp Cys Thr Pro Arg - # Asn Ile Gly Gly Asn Gly Tyr     Tyr     #   575     -      Ala Ala Val Gln Asp Asn Val Arg - # Leu Gly Arg Trp Ala Asp Val     Gly     #                590     -      Ala Gly Ile Arg Tyr Asp Tyr Arg - # Ser Thr His Ser Glu Asp Lys     Ser     #            605     -      Val Ser Thr Gly Thr His Arg Asn - # Leu Ser Trp Asn Ala Gly Val     Val     #        620     -      Leu Lys Pro Phe Thr Trp Met Asp - # Leu Thr Tyr Arg Ala Ser Thr     Gly     #    640     -      Phe Arg Leu Pro Ser Phe Ala Glu - # Met Tyr Gly Trp Arg Ala Gly     Glu     #   655     -      Ser Leu Lys Thr Leu Asp Leu Lys - # Pro Glu Lys Ser Phe Asn Arg     Glu     #                670     -      Ala Gly Ile Val Phe Lys Gly Asp - # Phe Gly Asn Leu Glu Ala Ser     Tyr     #            685     -      Phe Asn Asn Ala Tyr Arg Asp Leu - # Ile Ala Phe Gly Tyr Glu Thr     Arg     #        700     -      Thr Gln Asn Gly Gln Thr Ser Ala - # Ser Gly Asp Pro Gly Tyr Arg     Asn     #    720     -      Ala Gln Asn Ala Arg Ile Ala Gly - # Ile Asn Ile Leu Gly Lys Ile     Asp     #   735     -      Trp His Gly Val Trp Gly Gly Leu - # Pro Asp Gly Leu Tyr Ser Thr     Leu     #                750     -      Ala Tyr Asn Arg Ile Lys Val Lys - # Asp Ala Asp Ile Arg Ala Asp     Arg     #            765     -      Thr Phe Val Thr Ser Tyr Leu Phe - # Asp Ala Val Gln Pro Ser Arg     Tyr     #        780     -      Val Leu Gly Leu Gly Tyr Asp His - # Pro Asp Gly Ile Trp Gly Ile     Asn     #    800     -      Thr Met Phe Thr Tyr Ser Lys Ala - # Lys Ser Val Asp Glu Leu Leu     Gly     #   815     -      Ser Gln Ala Leu Leu Asn Gly Asn - # Ala Asn Ala Lys Lys Ala Ala     Ser     #                830     -      Arg Arg Thr Arg Pro Trp Tyr Val - # Thr Asp Val Ser Gly Tyr Tyr     Asn     #            845     -      Ile Lys Lys His Leu Thr Leu Arg - # Ala Gly Val Tyr Asn Leu Leu     Asn     #        860     -      Tyr Arg Tyr Val Thr Trp Glu Asn - # Val Arg Gln Thr Ala Gly Gly     Ala     #    880     -      Val Asn Gln His Lys Asn Val Gly - # Val Tyr Asn Arg Tyr Ala Ala     Pro     #   895     -      Gly Arg Asn Tyr Thr Phe Ser Leu - # Glu Met Lys Phe     #                905     - (2) INFORMATION FOR SEQ ID NO:95:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 911 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:95:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met Gln Gln Gln His Leu Phe Arg - # Leu Asn Ile Leu Cys Leu Ser     Leu     #   15     -      Met Thr Ala Leu Pro Ala Tyr Ala - # Glu Asn Val Gln Ala Gly Gln     Ala     #                 30     -      Gln Glu Lys Gln Leu Asp Thr Ile - # Gln Val Lys Ala Lys Lys Gln     Lys     #             45     -      Thr Arg Arg Asp Asn Glu Val Thr - # Gly Leu Gly Lys Leu Val Lys     Thr     #         60     -      Ala Asp Thr Leu Ser Lys Glu Gln - # Val Leu Asp Ile Arg Asp Leu     Thr     #     80     -      Arg Tyr Asp Pro Gly Ile Ala Val - # Val Glu Gln Gly Arg Gly Ala     Ser     #   95     -      Ser Gly Tyr Ser Ile Arg Gly Met - # Asp Lys Asn Arg Val Ser Leu     Thr     #                110     -      Val Asp Gly Leu Ala Gln Ile Gln - # Ser Tyr Thr Ala Gln Ala Ala     Leu     #            125     -      Gly Gly Thr Arg Thr Ala Gly Ser - # Ser Gly Ala Ile Asn Glu Ile     Glu     #        140     -      Tyr Glu Asn Val Lys Ala Val Glu - # Ile Ser Lys Gly Ser Asn Ser     Val     #    160     -      Glu Gln Gly Ser Gly Ala Leu Ala - # Gly Ser Val Ala Phe Gln Thr     Lys     #   175     -      Thr Ala Asp Asp Val Ile Gly Glu - # Gly Arg Gln Trp Gly Ile Gln     Ser     #                190     -      Lys Thr Ala Tyr Ser Gly Lys Asn - # Arg Gly Leu Thr Gln Ser Ile     Ala     #            205     -      Leu Ala Gly Arg Ile Gly Gly Ala - # Glu Ala Leu Leu Ile His Thr     Gly     #        220     -      Arg Arg Ala Gly Glu Ile Arg Ala - # His Glu Asp Ala Gly Arg Gly     Val     #    240     -      Gln Ser Phe Asn Arg Leu Val Pro - # Val Glu Asp Ser Ser Glu Tyr     Ala     #   255     -      Tyr Phe Ile Val Glu Asp Glu Cys - # Glu Gly Lys Asn Tyr Glu Thr     Cys     #                270     -      Lys Ser Lys Pro Lys Lys Asp Val - # Val Gly Lys Asp Glu Arg Gln     Thr     #            285     -      Val Ser Thr Arg Asp Tyr Thr Gly - # Pro Asn Arg Phe Leu Ala Asp     Pro     #        300     -      Leu Ser Tyr Glu Ser Arg Ser Trp - # Leu Phe Arg Pro Gly Phe Arg     Phe     #    320     -      Glu Asn Lys Arg His Tyr Ile Gly - # Gly Ile Leu Glu His Thr Gln     Gln     #   335     -      Thr Phe Asp Thr Arg Asp Met Thr - # Val Pro Ala Phe Leu Thr Lys     Ala     #                350     -      Val Phe Asp Ala Asn Ser Lys Gln - # Ala Gly Ser Leu Pro Gly Asn     Gly     #            365     -      Lys Tyr Ala Gly Asn His Lys Tyr - # Gly Gly Leu Phe Thr Asn Gly     Glu     #        380     -      Asn Gly Ala Leu Val Gly Ala Glu - # Tyr Gly Thr Gly Val Phe Tyr     Asp     #    400     -      Glu Thr His Thr Lys Ser Arg Tyr - # Gly Leu Glu Tyr Val Tyr Thr     Asn     #   415     -      Ala Asp Lys Asp Thr Trp Ala Asp - # Tyr Ala Arg Leu Ser Tyr Asp     Arg     #                430     -      Gln Gly Ile Gly Leu Asp Asn His - # Phe Gln Gln Thr His Cys Ser     Ala     #            445     -      Asp Gly Ser Asp Lys Tyr Cys Arg - # Pro Ser Ala Asp Lys Pro Phe     Ser     #        460     -      Tyr Tyr Lys Ser Asp Arg Val Ile - # Tyr Gly Glu Ser His Arg Leu     Leu     #    480     -      Gln Ala Ala Phe Lys Lys Ser Phe - # Asp Thr Ala Lys Ile Arg His     Asn     #   495     -      Leu Ser Val Asn Leu Gly Phe Asp - # Arg Phe Asp Ser Asn Leu Arg     His     #                510     -      Gln Asp Tyr Tyr Tyr Gln His Ala - # Asn Arg Ala Tyr Ser Ser Lys     Thr     #            525     -      Pro Pro Lys Thr Ala Asn Pro Asn - # Gly Asp Lys Ser Lys Pro Tyr     Trp     #        540     -      Val Ser Ile Gly Gly Gly Asn Val - # Val Thr Gly Gln Ile Cys Leu     Phe     #    560     -      Gly Asn Asn Thr Tyr Thr Asp Cys - # Thr Pro Arg Ser Ile Asn Gly     Lys     #   575     -      Ser Tyr Tyr Ala Ala Val Arg Asp - # Asn Val Arg Leu Gly Arg Trp     Ala     #                590     -      Asp Val Gly Ala Gly Leu Arg Tyr - # Asp Tyr Arg Ser Thr His Ser     Asp     #            605     -      Asp Gly Ser Val Ser Thr Gly Thr - # His Arg Thr Leu Ser Trp Asn     Ala     #        620     -      Gly Ile Val Leu Lys Pro Ala Asp - # Trp Leu Asp Leu Thr Tyr Arg     Thr     #    640     -      Ser Thr Gly Phe Arg Leu Pro Ser - # Phe Ala Glu Met Tyr Gly Trp     Arg     #   655     -      Ser Gly Val Gln Ser Lys Ala Val - # Lys Ile Asp Pro Glu Lys Ser     Phe     #                670     -      Asn Lys Glu Ala Gly Ile Val Phe - # Lys Gly Asp Phe Gly Asn Leu     Glu     #            685     -      Ala Ser Trp Phe Asn Asn Ala Tyr - # Arg Asp Leu Ile Val Arg Gly     Tyr     #        700     -      Glu Ala Gln Ile Lys Asn Gly Lys - # Glu Glu Ala Lys Gly Asp Pro     Ala     #    720     -      Tyr Leu Asn Ala Gln Ser Ala Arg - # Ile Thr Gly Ile Asn Ile Leu     Gly     #   735     -      Lys Ile Asp Trp Asn Gly Val Trp - # Asp Lys Leu Pro Glu Gly Trp     Tyr     #                750     -      Ser Thr Phe Ala Tyr Asn Arg Val - # His Val Arg Asp Ile Lys Lys     Arg     #            765     -      Ala Asp Arg Thr Asp Ile Gln Ser - # His Leu Phe Asp Ala Ile Gln     Pro     #        780     -      Ser Arg Tyr Val Val Gly Leu Gly - # Tyr Asp Gln Pro Glu Gly Lys     Trp     #    800     -      Gly Val Asn Gly Met Leu Thr Tyr - # Ser Lys Ala Lys Glu Ile Thr     Glu     #   815     -      Leu Leu Gly Ser Arg Ala Leu Leu - # Asn Gly Asn Ser Arg Asn Thr     Lys     #                830     -      Ala Thr Ala Arg Arg Thr Arg Pro - # Trp Tyr Ile Val Asp Val Ser     Gly     #            845     -      Tyr Tyr Thr Ile Lys Lys His Phe - # Thr Leu Arg Ala Gly Val Tyr     Asn     #        860     -      Leu Leu Asn Tyr Arg Tyr Val Thr - # Trp Glu Asn Val Arg Gln Thr     Ala     #    880     -      Gly Gly Ala Val Asn Gln His Lys - # Asn Val Gly Val Tyr Asn Arg     Tyr     #   895     -      Ala Ala Pro Gly Arg Asn Tyr Thr - # Phe Ser Leu Glu Met Lys Phe     #                910     - (2) INFORMATION FOR SEQ ID NO:96:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 915 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:96:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met Gln Gln Gln His Leu Phe Arg - # Leu Asn Ile Leu Cys Leu Ser     Leu     #   15     -      Met Thr Ala Leu Pro Ala Tyr Ala - # Glu Asn Val Gln Ala Gly Gln     Ala     #                 30     -      Gln Glu Lys Gln Leu Asp Thr Ile - # Gln Val Lys Ala Lys Lys Gln     Lys     #             45     -      Thr Arg Arg Asp Asn Glu Val Thr - # Gly Leu Gly Lys Leu Val Lys     Thr     #         60     -      Ala Asp Thr Leu Ser Lys Glu Gln - # Val Leu Asp Ile Arg Asp Leu     Thr     #     80     -      Arg Tyr Asp Pro Gly Ile Ala Val - # Val Glu Gln Gly Arg Gly Ala     Ser     #   95     -      Ser Gly Tyr Ser Ile Arg Gly Met - # Asp Lys Asn Arg Val Ser Leu     Thr     #                110     -      Val Asp Gly Leu Ala Gln Ile Gln - # Ser Tyr Thr Ala Gln Ala Ala     Leu     #            125     -      Gly Gly Thr Arg Thr Ala Gly Ser - # Ser Gly Ala Ile Asn Glu Ile     Glu     #        140     -      Tyr Glu Asn Val Lys Ala Val Glu - # Ile Ser Lys Gly Ser Asn Ser     Val     #    160     -      Glu Gln Gly Ser Gly Ala Leu Ala - # Gly Ser Val Ala Phe Gln Thr     Lys     #   175     -      Thr Ala Asp Asp Val Ile Gly Glu - # Gly Arg Gln Trp Gly Ile Gln     Ser     #                190     -      Lys Thr Ala Tyr Ser Gly Lys Asn - # Arg Gly Leu Thr Gln Ser Ile     Ala     #            205     -      Leu Ala Gly Arg Ile Gly Gly Ala - # Glu Ala Leu Leu Ile Arg Thr     Gly     #        220     -      Arg His Ala Gly Glu Ile Arg Ala - # His Glu Ala Ala Gly Arg Gly     Val     #    240     -      Gln Ser Phe Asn Arg Leu Ala Pro - # Val Asp Asp Gly Ser Lys Tyr     Ala     #   255     -      Tyr Phe Ile Val Glu Glu Glu Cys - # Lys Asn Gly Gly His Glu Lys     Cys     #                270     -      Lys Ala Asn Pro Lys Lys Asp Val - # Val Gly Glu Asp Lys Arg Gln     Thr     #            285     -      Val Ser Thr Arg Asp Tyr Thr Gly - # Pro Asn Arg Phe Leu Ala Asp     Pro     #        300     -      Leu Ser Tyr Glu Ser Arg Ser Trp - # Leu Phe Arg Pro Gly Phe Arg     Phe     #    320     -      Glu Asn Lys Arg His Tyr Ile Gly - # Gly Ile Leu Glu Arg Thr Gln     Gln     #   335     -      Thr Phe Asp Thr Arg Asp Met Thr - # Val Pro Ala Phe Leu Thr Lys     Ala     #                350     -      Val Phe Asp Ala Asn Gln Lys Gln - # Ala Gly Ser Leu Arg Gly Asn     Gly     #            365     -      Lys Tyr Ala Gly Asn His Lys Tyr - # Gly Gly Leu Phe Thr Ser Gly     Glu     #        380     -      Asn Asn Ala Pro Val Gly Ala Glu - # Tyr Gly Thr Gly Val Phe Tyr     Asp     #    400     -      Glu Thr His Thr Lys Ser Arg Tyr - # Gly Leu Glu Tyr Val Tyr Thr     Asn     #   415     -      Ala Asp Lys Asp Thr Trp Ala Asp - # Tyr Ala Arg Leu Ser Tyr Asp     Arg     #                430     -      Gln Gly Ile Gly Leu Asp Asn His - # Phe Gln Gln Thr His Cys Ser     Ala     #            445     -      Asp Gly Ser Asp Lys Tyr Cys Arg - # Pro Ser Ala Asp Lys Pro Phe     Ser     #        460     -      Tyr Tyr Lys Ser Asp Arg Val Ile - # Tyr Gly Glu Ser His Lys Leu     Leu     #    480     -      Gln Ala Ala Phe Lys Lys Ser Phe - # Asp Thr Ala Lys Ile Arg His     Asn     #   495     -      Leu Ser Val Asn Leu Gly Tyr Asp - # Arg Phe Gly Ser Asn Leu Arg     His     #                510     -      Gln Asp Tyr Tyr Tyr Gln Ser Ala - # Asn Arg Ala Tyr Ser Leu Lys     Thr     #            525     -      Pro Pro Gln Asn Asn Gly Lys Lys - # Thr Ser Pro Asn Gly Arg Glu     Lys     #        540     -      Asn Pro Tyr Trp Val Ser Ile Gly - # Arg Gly Asn Val Val Thr Arg     Gln     #    560     -      Ile Cys Leu Phe Gly Asn Asn Thr - # Tyr Thr Asp Cys Thr Pro Arg     Ser     #   575     -      Ile Asn Gly Lys Ser Tyr Tyr Ala - # Ala Val Arg Asp Asn Val Arg     Leu     #                590     -      Gly Arg Trp Ala Asp Val Gly Ala - # Gly Leu Arg Tyr Asp Tyr Arg     Ser     #            605     -      Thr His Ser Asp Asp Gly Ser Val - # Ser Thr Gly Thr His Arg Thr     Leu     #        620     -      Ser Trp Asn Ala Gly Ile Val Leu - # Lys Pro Ala Asp Trp Leu Asp     Leu     #    640     -      Thr Tyr Arg Thr Ser Thr Gly Phe - # Arg Leu Pro Ser Phe Ala Glu     Met     #   655     -      Tyr Gly Trp Arg Ser Gly Asp Lys - # Ile Lys Ala Val Lys Ile Asp     Pro     #                670     -      Glu Lys Ser Phe Asn Lys Glu Ala - # Gly Ile Val Phe Lys Gly Asp     Phe     #            685     -      Gly Asn Leu Glu Ala Ser Trp Phe - # Asn Asn Ala Tyr Arg Asp Leu     Ile     #        700     -      Val Arg Gly Tyr Glu Ala Gln Ile - # Lys Asp Gly Lys Glu Gln Val     Lys     #    720     -      Gly Asn Pro Ala Tyr Leu Asn Ala - # Gln Ser Ala Arg Ile Thr Gly     Ile     #   735     -      Asn Ile Leu Gly Lys Ile Asp Trp - # Asn Gly Val Trp Asp Lys Leu     Pro     #                750     -      Glu Gly Trp Tyr Ser Thr Phe Ala - # Tyr Asn Arg Val Arg Val Arg     Asp     #            765     -      Ile Lys Lys Arg Ala Asp Arg Thr - # Asp Ile Gln Ser His Leu Phe     Asp     #        780     -      Ala Ile Gln Pro Ser Arg Tyr Val - # Val Gly Ser Gly Tyr Asp Gln     Pro     #    800     -      Glu Gly Lys Trp Gly Val Asn Gly - # Met Leu Thr Tyr Ser Lys Ala     Lys     #   815     -      Glu Ile Thr Glu Leu Leu Gly Ser - # Arg Ala Leu Leu Asn Gly Asn     Ser     #                830     -      Arg Asn Thr Lys Ala Thr Ala Arg - # Arg Thr Arg Pro Trp Tyr Ile     Val     #            845     -      Asp Val Ser Gly Tyr Tyr Thr Val - # Lys Lys His Phe Thr Leu Arg     Ala     #        860     -      Gly Val Tyr Asn Leu Leu Asn His - # Arg Tyr Val Thr Trp Glu Asn     Val     #    880     -      Arg Gln Thr Ala Ala Gly Ala Val - # Asn Gln His Lys Asn Val Gly     Val     #   895     -      Tyr Asn Arg Tyr Ala Ala Pro Gly - # Arg Asn Tyr Thr Phe Ser Leu     Glu     #                910     -      Met Lys Phe                  915     - (2) INFORMATION FOR SEQ ID NO:97:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 598 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:97:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met Asn Asn Pro Leu Val Asn Gln - # Ala Ala Met Val Leu Pro Val     Phe     #   15     -      Leu Leu Ser Ala Cys Leu Gly Gly - # Gly Gly Ser Phe Asp Leu Asp     Ser     #                 30     -      Val Glu Thr Val Gln Asp Met His - # Ser Lys Pro Lys Tyr Glu Asp     Glu     #             45     -      Lys Ser Gln Pro Glu Ser Gln Gln - # Asp Val Ser Glu Asn Ser Gly     Ala     #         60     -      Ala Tyr Gly Phe Ala Val Lys Leu - # Pro Arg Arg Asn Ala His Phe     Asn     #     80     -      Pro Lys Tyr Lys Glu Lys His Lys - # Pro Leu Gly Ser Met Asp Trp     Lys     #   95     -      Lys Leu Gln Arg Gly Glu Pro Asn - # Ser Phe Ser Glu Arg Asp Glu     Leu     #                110     -      Glu Lys Lys Arg Gly Ser Ser Glu - # Leu Ile Glu Ser Lys Trp Glu     Asp     #            125     -      Gly Gln Ser Arg Val Val Gly Tyr - # Thr Asn Phe Thr Tyr Val Arg     Ser     #        140     -      Gly Tyr Val Tyr Leu Asn Lys Asn - # Asn Ile Asp Ile Lys Asn Asn     Ile     #    160     -      Val Leu Phe Gly Pro Asp Gly Tyr - # Leu Tyr Tyr Lys Gly Lys Glu     Pro     #   175     -      Ser Lys Glu Leu Pro Ser Glu Lys - # Ile Thr Tyr Lys Gly Thr Trp     Asp     #                190     -      Tyr Val Thr Asp Ala Met Glu Lys - # Gln Arg Phe Glu Gly Leu Gly     Ser     #            205     -      Ala Ala Gly Gly Asp Lys Ser Gly - # Ala Leu Ser Ala Leu Glu Glu     Gly     #        220     -      Val Leu Arg Asn Gln Ala Glu Ala - # Ser Ser Gly His Thr Asp Phe     Gly     #    240     -      Met Thr Ser Glu Phe Glu Val Asp - # Phe Ser Asp Lys Thr Ile Lys     Gly     #   255     -      Thr Leu Tyr Arg Asn Asn Arg Ile - # Thr Gln Asn Asn Ser Glu Asn     Lys     #                270     -      Gln Ile Lys Thr Thr Arg Tyr Thr - # Ile Gln Ala Thr Leu His Gly     Asn     #            285     -      Arg Phe Lys Gly Lys Ala Leu Ala - # Ala Asp Lys Gly Ala Thr Asn     Gly     #        300     -      Ser His Pro Phe Ile Ser Asp Ser - # Asp Ser Leu Glu Gly Gly Phe     Tyr     #    320     -      Gly Pro Lys Gly Glu Glu Leu Ala - # Gly Lys Phe Leu Ser Asn Asp     Asn     #   335     -      Lys Val Ala Ala Val Phe Gly Ala - # Lys Gln Lys Asp Lys Lys Asp     Gly     #                350     -      Glu Asn Ala Ala Gly Pro Ala Thr - # Glu Val Ile Asp Ala Tyr Arg     Ile     #            365     -      Thr Gly Glu Glu Phe Lys Lys Glu - # Gln Ile Asp Ser Phe Gly Asp     Val     #        380     -      Lys Lys Leu Leu Val Asp Gly Val - # Glu Leu Ser Leu Leu Pro Ser     Glu     #    400     -      Gly Asn Lys Ala Ala Phe Gln His - # Glu Ile Glu Gln Asn Gly Val     Lys     #   415     -      Ala Thr Val Cys Cys Ser Asn Leu - # Asp Tyr Met Ser Phe Gly Lys     Leu     #                430     -      Ser Lys Glu Asn Lys Asp Asp Met - # Phe Leu Gln Gly Val Arg Thr     Pro     #            445     -      Val Ser Asp Val Ala Ala Arg Thr - # Glu Ala Asn Ala Lys Tyr Arg     Gly     #        460     -      Thr Trp Tyr Gly Tyr Ile Ala Asn - # Gly Thr Ser Trp Ser Gly Glu     Ala     #    480     -      Ser Asn Gln Glu Gly Gly Asn Arg - # Ala Glu Phe Asp Val Asp Phe     Ser     #   495     -      Thr Lys Lys Ile Ser Gly Thr Leu - # Thr Ala Lys Asp Arg Thr Ser     Pro     #                510     -      Ala Phe Thr Ile Thr Ala Met Ile - # Lys Asp Asn Gly Phe Ser Gly     Val     #            525     -      Ala Lys Thr Gly Glu Asn Gly Phe - # Ala Leu Asp Pro Gln Asn Thr     Gly     #        540     -      Asn Ser His Tyr Thr His Ile Glu - # Ala Thr Val Ser Gly Gly Phe     Tyr     #    560     -      Gly Lys Asn Ala Ile Glu Met Gly - # Gly Ser Phe Ser Phe Pro Gly     Asn     #   575     -      Ala Pro Glu Gly Lys Gln Glu Lys - # Ala Ser Val Val Phe Gly Ala     Lys     #                590     -      Arg Gln Gln Leu Val Gln                  595     - (2) INFORMATION FOR SEQ ID NO:98:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 711 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:98:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met Asn Asn Pro Leu Val Asn Gln - # Ala Ala Met Val Leu Pro Val     Phe     #   15     -      Leu Leu Ser Ala Cys Leu Gly Gly - # Gly Gly Ser Phe Asp Leu Asp     Ser     #                 30     -      Val Asp Thr Glu Ala Pro Arg Pro - # Ala Pro Lys Tyr Gln Asp Val     Ser     #             45     -      Ser Glu Lys Pro Gln Ala Gln Lys - # Asp Gln Gly Gly Tyr Gly Phe     Ala     #         60     -      Met Arg Leu Lys Arg Arg Asn Trp - # Tyr Pro Gly Ala Glu Glu Ser     Glu     #     80     -      Val Lys Leu Asn Glu Ser Asp Trp - # Glu Ala Thr Gly Leu Pro Thr     Lys     #   95     -      Pro Lys Glu Leu Pro Lys Arg Gln - # Lys Ser Val Ile Glu Lys Val     Glu     #                110     -      Thr Asp Gly Asp Ser Asp Ile Tyr - # Ser Ser Pro Tyr Leu Thr Pro     Ser     #            125     -      Asn His Gln Asn Gly Ser Ala Gly - # Asn Gly Val Asn Gln Pro Lys     Asn     #        140     -      Gln Ala Thr Gly His Glu Asn Phe - # Gln Tyr Val Tyr Ser Gly Trp     Phe     #    160     -      Tyr Lys His Ala Ala Ser Glu Lys - # Asp Phe Ser Asn Lys Lys Ile     Lys     #   175     -      Ser Gly Asp Asp Gly Tyr Ile Phe - # Tyr His Gly Glu Lys Pro Ser     Arg     #                190     -      Gln Leu Pro Ala Ser Gly Lys Val - # Ile Tyr Lys Gly Val Trp His     Phe     #            205     -      Val Thr Asp Thr Lys Lys Gly Gln - # Asp Phe Arg Glu Ile Ile Gln     Pro     #        220     -      Ser Lys Lys Gln Gly Asp Arg Tyr - # Ser Gly Phe Ser Gly Asp Gly     Ser     #    240     -      Glu Glu Tyr Ser Asn Lys Asn Glu - # Ser Thr Leu Lys Asp Asp His     Glu     #   255     -      Gly Tyr Gly Phe Thr Ser Asn Leu - # Glu Val Asp Phe Gly Asn Lys     Lys     #                270     -      Leu Thr Gly Lys Leu Ile Arg Asn - # Asn Ala Ser Leu Asn Asn Asn     Thr     #            285     -      Asn Asn Asp Lys His Thr Thr Gln - # Tyr Tyr Ser Leu Asp Ala Gln     Ile     #        300     -      Thr Gly Asn Arg Phe Asn Gly Thr - # Ala Thr Ala Thr Asp Lys Lys     Glu     #    320     -      Asn Glu Thr Lys Leu His Pro Phe - # Val Ser Asp Ser Ser Ser Leu     Ser     #   335     -      Gly Gly Phe Phe Gly Pro Gln Gly - # Glu Glu Leu Gly Phe Arg Phe     Leu     #                350     -      Ser Asp Asp Gln Lys Val Ala Val - # Val Gly Ser Ala Lys Thr Lys     Asp     #            365     -      Lys Leu Glu Asn Gly Ala Ala Ala - # Ser Gly Ser Thr Gly Ala Ala     Ala     #        380     -      Ser Gly Gly Ala Ala Gly Thr Ser - # Ser Glu Asn Ser Lys Leu Thr     Thr     #    400     -      Val Leu Asp Ala Val Glu Leu Thr - # Leu Asn Asp Lys Lys Ile Lys     Asn     #   415     -      Leu Asp Asn Phe Ser Asn Ala Ala - # Gln Leu Val Val Asp Gly Ile     Met     #                430     -      Ile Pro Leu Leu Pro Lys Asp Ser - # Glu Ser Gly Asn Thr Gln Ala     Asp     #            445     -      Lys Gly Lys Asn Gly Gly Thr Glu - # Phe Thr Arg Lys Phe Glu His     Thr     #        460     -      Pro Glu Ser Asp Lys Lys Asp Ala - # Gln Ala Gly Thr Gln Thr Asn     Gly     #    480     -      Ala Gln Thr Ala Ser Asn Thr Ala - # Gly Asp Thr Asn Gly Lys Thr     Lys     #   495     -      Thr Tyr Glu Val Glu Val Cys Cys - # Ser Asn Leu Asn Tyr Leu Lys     Tyr     #                510     -      Gly Met Leu Thr Arg Lys Asn Ser - # Lys Ser Ala Met Gln Ala Gly     Gly     #            525     -      Asn Ser Ser Gln Ala Asp Ala Lys - # Thr Glu Gln Val Glu Gln Ser     Met     #        540     -      Phe Leu Gln Gly Glu Arg Thr Asp - # Glu Lys Glu Ile Pro Thr Asp     Gln     #    560     -      Asn Val Val Tyr Arg Gly Ser Trp - # Tyr Gly His Ile Ala Asn Gly     Thr     #   575     -      Ser Trp Ser Gly Asn Ala Ser Asp - # Lys Glu Gly Gly Asn Arg Ala     Glu     #                590     -      Phe Thr Val Asn Phe Ala Asp Lys - # Lys Ile Thr Gly Lys Leu Thr     Ala     #            605     -      Glu Asn Arg Gln Ala Gln Thr Phe - # Thr Ile Glu Gly Met Ile Gln     Gly     #        620     -      Asn Gly Phe Glu Gly Thr Ala Lys - # Thr Ala Glu Ser Gly Phe Asp     Leu     #    640     -      Asp Gln Lys Asn Thr Thr Arg Thr - # Pro Lys Ala Tyr Ile Thr Asp     Ala     #   655     -      Lys Val Lys Gly Gly Phe Tyr Gly - # Pro Lys Ala Glu Glu Leu Gly     Gly     #                670     -      Trp Phe Ala Tyr Pro Gly Asp Lys - # Gln Thr Glu Lys Ala Thr Ala     Thr     #            685     -      Ser Ser Asp Gly Asn Ser Ala Ser - # Ser Ala Thr Val Val Phe Gly     Ala     #        700     -      Lys Arg Gln Gln Pro Val Gln     #    710     - (2) INFORMATION FOR SEQ ID NO:99:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 546 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:99:(xi) SEQUENCE DESCRIPTION: SEQ     -      Met His Phe Lys Leu Asn Pro Tyr - # Ala Leu Ala Phe Thr Ser Leu     Phe     #   15     -      Leu Val Ala Cys Ser Gly Gly Lys - # Gly Ser Phe Asp Leu Glu Asp     Val     #                 30     -      Arg Pro Asn Lys Thr Thr Gly Val - # Ser Lys Glu Glu Tyr Lys Asp     Val     #             45     -      Glu Thr Ala Lys Lys Glu Lys Glu - # Gln Leu Gly Glu Leu Met Glu     Pro     #         60     -      Ala Leu Gly Tyr Val Val Lys Val - # Pro Val Ser Ser Phe Glu Asn     Lys     #     80     -      Lys Val Asp Ile Ser Asp Ile Glu - # Val Ile Thr Asn Gly Asn Leu     Asp     #   95     -      Asp Val Pro Tyr Lys Ala Asn Ser - # Ser Lys Tyr Asn Tyr Pro Asp     Ile     #                110     -      Lys Thr Lys Asp Ser Ser Leu Gln - # Tyr Val Arg Ser Gly Tyr Val     Ile     #            125     -      Asp Gly Glu His Ser Gly Ser Asn - # Glu Lys Gly Tyr Val Tyr Tyr     Lys     #        140     -      Gly Asn Ser Pro Ala Lys Glu Leu - # Pro Val Asn Gln Leu Leu Thr     Tyr     #    160     -      Thr Gly Ser Trp Asp Phe Thr Ser - # Asn Ala Asn Leu Asn Asn Glu     Glu     #   175     -      Gly Arg Pro Asn Tyr Leu Asn Asp - # Asp Tyr Tyr Thr Lys Phe Ile     Gly     #                190     -      Lys Arg Val Gly Leu Val Ser Gly - # Asp Ala Lys Pro Ala Lys His     Lys     #            205     -      Tyr Thr Ser Gln Phe Glu Val Asp - # Phe Ala Thr Lys Lys Met Thr     Gly     #        220     -      Lys Ser Asp Lys Glu Lys Thr Ile - # Tyr Thr Val Asn Ala Asp Ile     Arg     #    240     -      Gly Asn Arg Phe Thr Gly Ala Ala - # Thr Ala Ser Asp Lys Asn Lys     Gly     #   255     -      Lys Gly Glu Ser Tyr Asn Phe Phe - # Ser Ala Asp Ser Gln Ser Leu     Glu     #                270     -      Gly Gly Phe Tyr Gly Pro Lys Ala - # Glu Glu Met Ala Gly Lys Phe     Val     #            285     -      Ala Asn Asp Lys Ser Leu Phe Ala - # Val Phe Ser Ala Lys His Asn     Gly     #        300     -      Ser Asn Val Asn Thr Val Arg Ile - # Ile Asp Ala Ser Lys Ile Asp     Leu     #    320     -      Thr Asn Phe Ser Ile Ser Glu Leu - # Asn Asn Phe Gly Asp Ala Ser     Val     #   335     -      Leu Ile Ile Asp Gly Lys Lys Ile - # Lys Leu Ala Gly Ser Gly Phe     Thr     #                350     -      Asn Lys His Thr Ile Glu Ile Asn - # Gly Lys Thr Met Val Ala Val     Ala     #            365     -      Cys Cys Ser Asn Leu Glu Tyr Met - # Lys Phe Gly Gln Leu Trp Gln     Gln     #        380     -      Ala Glu Gly Gly Lys Pro Glu Asn - # Asn Ser Leu Phe Leu Gln Gly     Glu     #    400     -      Arg Thr Ala Thr Asp Lys Met Pro - # Lys Gly Gly Asn Tyr Lys Tyr     Ile     #   415     -      Gly Thr Trp Asp Ala Gln Val Ser - # Lys Glu Asn Asn Trp Val Ala     Thr     #                430     -      Ala Asp Asp Asp Arg Lys Ala Gly - # Tyr Arg Thr Glu Phe Asp Val     Asp     #            445     -      Phe Gly Asn Lys Asn Leu Ser Gly - # Lys Leu Phe Asp Lys Asn Gly     Val     #        460     -      Asn Pro Val Phe Thr Val Asp Ala - # Lys Ile Asp Gly Asn Gly Phe     Thr     #    480     -      Gly Lys Ala Lys Thr Ser Asp Glu - # Gly Phe Ala Leu Asp Ser Gly     Ser     #   495     -      Ser Arg Tyr Glu Asn Val Lys Phe - # Asn Asp Val Ala Val Ser Gly     Gly     #                510     -      Phe Tyr Gly Pro Thr Ala Ala Glu - # Leu Gly Gly Gln Phe His His     Lys     #            525     -      Ser Glu Asn Gly Ser Val Gly Ala - # Val Phe Gly Ala Lys Gln Gln     Val     #        540     -      Lys Lys          545     - (2) INFORMATION FOR SEQ ID NO:100:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 593 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:100:xi) SEQUENCE DESCRIPTION: SEQ     -      Met His Phe Lys Leu Asn Pro Tyr - # Ala Leu Ala Phe Thr Ser Leu     Phe     #   15     -      Leu Val Ala Cys Ser Gly Gly Lys - # Gly Ser Phe Asp Leu Glu Asp     Val     #                 30     -      Arg Pro Asn Gln Thr Ala Lys Ala - # Glu Lys Ala Thr Thr Ser Tyr     Gln     #             45     -      Asp Glu Glu Thr Lys Lys Lys Thr - # Lys Glu Glu Leu Asp Lys Leu     Met     #         60     -      Glu Pro Ala Leu Gly Tyr Glu Thr - # Gln Ile Leu Arg Arg Asn Lys     Ala     #     80     -      Pro Lys Thr Glu Thr Gly Glu Lys - # Arg Asn Glu Arg Val Val Glu     Leu     #   95     -      Ser Glu Asp Lys Ile Thr Lys Leu - # Tyr Gln Glu Ser Val Glu Ile     Ile     #                110     -      Pro His Leu Asp Glu Leu Asn Gly - # Lys Thr Thr Ser Asn Asp Val     Tyr     #            125     -      His Ser His Asp Ser Lys Arg Leu - # Asp Lys Asn Arg Asp Leu Lys     Tyr     #        140     -      Val Arg Ser Gly Tyr Val Tyr Asp - # Gly Ser Phe Asn Glu Ile Arg     Arg     #    160     -      Asn Asp Ser Gly Phe His Val Phe - # Lys Gln Gly Ile Asp Gly Tyr     Val     #   175     -      Tyr Tyr Leu Gly Val Thr Pro Ser - # Lys Glu Leu Pro Lys Gly Lys     Val     #                190     -      Ile Ser Tyr Lys Gly Thr Trp Asp - # Phe Val Ser Asn Ile Asn Leu     Glu     #            205     -      Arg Glu Ile Asp Gly Phe Asp Thr - # Ser Gly Asp Gly Lys Asn Val     Ser     #        220     -      Ala Thr Ser Ile Thr Glu Thr Val - # Asn Arg Asp His Lys Val Gly     Glu     #    240     -      Lys Leu Gly Asp Asn Glu Val Lys - # Gly Val Ala His Ser Ser Glu     Phe     #   255     -      Ala Val Asp Phe Asp Asn Lys Lys - # Leu Thr Gly Ser Leu Tyr Arg     Asn     #                270     -      Gly Tyr Ile Asn Arg Asn Lys Ala - # Gln Glu Val Thr Lys Arg Tyr     Ser     #            285     -      Ile Glu Ala Asp Ile Ala Gly Asn - # Arg Phe Arg Gly Lys Ala Lys     Ala     #        300     -      Glu Lys Ala Gly Asp Pro Ile Phe - # Thr Asp Ser Asn Tyr Leu Glu     Gly     #    320     -      Gly Phe Tyr Gly Pro Lys Ala Glu - # Glu Met Ala Gly Lys Phe Phe     Thr     #   335     -      Asn Asn Lys Ser Leu Phe Ala Val - # Phe Ala Ala Lys Ser Glu Asn     Gly     #                350     -      Glu Thr Thr Thr Glu Arg Ile Ile - # Asp Ala Thr Lys Ile Asp Leu     Thr     #            365     -      Gln Phe Asn Ala Lys Glu Leu Asn - # Asn Phe Gly Asp Ala Ser Val     Leu     #        380     -      Ile Ile Asp Gly Gln Lys Ile Asp - # Leu Ala Gly Val Asn Phe Lys     Asn     #    400     -      Ser Lys Thr Val Glu Ile Asn Gly - # Lys Thr Met Val Ala Val Ala     Cys     #   415     -      Cys Ser Asn Leu Glu Tyr Met Lys - # Phe Gly Gln Leu Trp Gln Lys     Glu     #                430     -      Gly Lys Gln Gln Val Lys Asp Asn - # Ser Leu Phe Leu Gln Gly Glu     Arg     #            445     -      Thr Ala Thr Asp Lys Met Pro Ala - # Gly Gly Asn Tyr Lys Tyr Val     Gly     #        460     -      Thr Trp Asp Ala Leu Val Ser Lys - # Gly Thr Asn Trp Ile Ala Glu     Ala     #    480     -      Asp Asn Asn Arg Glu Ser Gly Tyr - # Arg Thr Glu Phe Asp Val Asn     Phe     #   495     -      Ser Asp Lys Lys Val Asn Gly Lys - # Leu Phe Asp Lys Gly Gly Val     Asn     #                510     -      Pro Val Phe Thr Val Asp Ala Thr - # Ile Asn Gly Asn Gly Phe Ile     Gly     #            525     -      Ser Ala Lys Thr Ser Asp Ser Gly - # Phe Ala Leu Asp Ala Gly Ser     Ser     #        540     -      Gln His Gly Asn Ala Val Phe Ser - # Asp Ile Lys Val Asn Gly Gly     Phe     #    560     -      Tyr Gly Pro Thr Ala Gly Glu Leu - # Gly Gly Gln Phe His His Lys     Ser     #   575     -      Asp Asn Gly Ser Val Gly Ala Val - # Phe Gly Ala Lys Arg Gln Ile     Glu     #                590     -      Lys     - (2) INFORMATION FOR SEQ ID NO:101:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 18 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:101:xi) SEQUENCE DESCRIPTION: SEQ     -      Glu Thr Gln Ser Ile Lys Asp Thr - # Lys Glu Ala Ile Ser Ser Glu     Val     #   15     -      Asp Thr     - (2) INFORMATION FOR SEQ ID NO:102:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 20 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:102:xi) SEQUENCE DESCRIPTION: SEQ     -      Leu Gln Leu Asn Leu Glu Lys Lys - # Ile Gln Gln Asn Trp Leu Thr     His     #   15     -      Gln Ile Ala Phe                      20     - (2) INFORMATION FOR SEQ ID NO:103:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 23 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:103:xi) SEQUENCE DESCRIPTION: SEQ     -      Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys Leu     Leu     #   15     -      Ile Ser Cys Tyr Val Lys Ala                      20     - (2) INFORMATION FOR SEQ ID NO:104:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 17 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO:104:xi) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu Leu     Ser     #   15     -      Ala     - (2) INFORMATION FOR SEQ ID NO: 105:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 5144 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     -     (ix) FEATURE:               (A) NAME/KEY: CDS               (B) LOCATION: join(192..69 - #5, 2135..4867)     #ID NO: 105:i) SEQUENCE DESCRIPTION: SEQ     - CAACATCTGC CCAAGCTATA TTCGTTAATG ATAAGCCTAT TAATGATAAG CC - #TATTAATG       60     - ATAAGAAAGA AATTTGTTTT ACGCCATTTT TCATATTTTA TCCATGAACT TA - #AAAAATTC      120     - TAAGTTGACA TTATTACAAA AAAAGAACAA TAATGCGAAT TATTATCAAT TT - #TGTATAAG      180     #GGT GGA CTT TCC TTT     230TA CCT CTT ATC TCT     #Val Pro Leu Ile Ser Gly Gly Leu Ser Phe     #            10     - TTA TTA AGT GCT TGT AGC GGA GGA GGG TCT TT - #T GAT GTA GAT AAC GTC      278     Leu Leu Ser Ala Cys Ser Gly Gly Gly Ser Ph - #e Asp Val Asp Asn Val     #     25     - TCT AAT CCC TCC TCT TCT AAA CCA CGT TAT CA - #A GAC GAT ACC TCG AAT      326     Ser Asn Pro Ser Ser Ser Lys Pro Arg Tyr Gl - #n Asp Asp Thr Ser Asn     # 45     - CAA AGA ACA AAA TCT GAT TTG CAA AAG TTG TC - #C ATT CCT TCT TTA GGG      374     Gln Arg Thr Lys Ser Asp Leu Gln Lys Leu Se - #r Ile Pro Ser Leu Gly     #                 60     - GGA GGG ATG AAG TTA GTG GCT CAG AAT CTT CT - #T GGT AAG AAA GAA CCT      422     Gly Gly Met Lys Leu Val Ala Gln Asn Leu Le - #u Gly Lys Lys Glu Pro     #             75     - AGT CTC TTA AAT AAT GAA GAT GGC TAT ATG AT - #A TTT TCC TCA CTT TCT      470     Ser Leu Leu Asn Asn Glu Asp Gly Tyr Met Il - #e Phe Ser Ser Leu Ser     #         90     - ACG ATT GAA GAG GAT GTT ACA AAA GAA AAT AA - #A TCT CAG GAA CCC ACT      518     Thr Ile Glu Glu Asp Val Thr Lys Glu Asn Ly - #s Ser Gln Glu Pro Thr     #    105     - ATT GGC TCA ATA GAC GAG CCT AGC AAA ACA AA - #T TCA CCC CAA AAT CAT      566     Ile Gly Ser Ile Asp Glu Pro Ser Lys Thr As - #n Ser Pro Gln Asn His     110                 1 - #15                 1 - #20                 1 -     #25     - CAT GGC AAT ATG TAT ATT CGG GTC TTT ATT AT - #A TTC AAT CGT GGC GTA      614     His Gly Asn Met Tyr Ile Arg Val Phe Ile Il - #e Phe Asn Arg Gly Val     #               140     - ATT CCT CAA ATG GCA AGT TTT ATT CAG GTT AC - #T ATG GAT ATG CGT ATT      662     Ile Pro Gln Met Ala Ser Phe Ile Gln Val Th - #r Met Asp Met Arg Ile     #           155     - ACT TTG GCA AGC AAA CAG CCA CTA CAT TAC CT - #G TAGATGGCGA AGCAACGTAT      715     Thr Leu Ala Ser Lys Gln Pro Leu His Tyr Le - #u     #       165     - AAAGGAACTT GGCACTTCAT CACCGCAACT GAAAATGGCA AAAAGTATTC TT - #TGTTCAGT      775     - AATGATAGCG GTCAAGCTTA TCGCAGACGT AGTGCAATTC CAGAAGATAT TG - #ATTTAGAA      835     - AAAAATGATT CAACTAATGG TGACAAGGGC TTAATAAGTG AATTTAGTGT CA - #ATTTTGGT      895     - ACAAAAAAGC TCACTGGAAA ACTTTATTAT AATGAAAGAG AAACAGAACT TA - #ATAAATCA      955     - AAAGATAGAA AACATACACT CTACAATCTA GAAGCTGAAG TGTATAGTAA CC - #GATTCAGG     1015     - GGTACAGTAA AGCCAACCGA AAAAGATTCT ACAGATCATC CCTTTACCAG CG - #AGGGAACA     1075     - TTAGAAGGTG GTTTTTATGG GCCTAAAGGT GAAGAACTAG GAGGAAAGTT TT - #TAGCTGGC     1135     - GATAAAAAAG TTTTTGGGGT ATTTAGTGCC AAAGAAACGG AAGAAACAAA AA - #AGAAAGCG     1195     - TTATCCAAGG AAACCTTAAT TGATGGCAAG CTAACTACTT TTAAAACAAC CA - #ATGCAACA     1255     - ACCAATGCAA CAGCCAATGC AACAACCAGT ACAACAGCCA GTACAACAAC CG - #ATGCAGAA     1315     - AACTTTACGA CGAAAGATAT ACCAAGTTTT GGTGAAGCTG ATTACCTTTT AA - #TTGATAAT     1375     - TACCCTGTTC CTCTTTTACC TGAGAGTGGT GATTTCATAA GTAGTAAGCA CC - #ATACTGTA     1435     - GGAAAGAAAA CCTATCAAGT AGAAGCATGT TGCAGTAATC TAAGCTATGT GA - #AATTTGGT     1495     - ATGTTTTATG AAGACCCACT TAAAGAAGAA AAAGACAAAG AAAAAGAAGA AG - #ACAAAGAA     1555     - AAACAAACGG CGGCAACGAC CAACACTTAT TATCAATTCT TATTAGGTCT CC - #GTACTGCC     1615     - AGTTCTGAAA TTCCTAAAAT GGGAAACGTG GAATATCGCG GTAATTGGTT TG - #GTTATATT     1675     - AGTGATGGCA CGACATCTTA CTCCCCCAGT GGTGATAAGG AACGCAATAA AA - #ATGCTCCC     1735     - GCCGATTTTA ATGTTGATTT TGTCAATAAA AAGCTAACAG GCACATTAAA AC - #GACACGAT     1795     - AATGGAAATA CCGTATTTAG TATTGAGGCA AACTTTAACA GTGGGAATGA CT - #TCACTGGT     1855     - AAAGCAACCG CAAAAGATTT AGTAATAGAT GGTAAAAGTA CACAAGCCAC AT - #CTAAAGTC     1915     - AATTTCACGG CAACAGTAAA AGGGGCATTT TATGGACCTG ATGCTTCTGA AT - #TAGGCGGT     1975     - TATTTCACCT ATAACGGAAA AAATCCTACA GCTACAAATT CCCCAACCGT AT - #CTTCACCA     2035     - TCCAATTCAG CAAATGCTCG TGCTGCCGTT GTGTTTGGAG CTAAAAAACA AG - #TAGACACA     2095     - ACCAACAAGT AGAAAAAACC AAATAATGGA ATACTAAAA ATG ACT AAA - # AAA CCC     2149     #       Met Thr Lys Lys Pro     #           170     - TAT TTT CGC CTA AGT ATT ATT TCT TGT CTT TT - #A ATT TCA TGC TAT GTA     2197     Tyr Phe Arg Leu Ser Ile Ile Ser Cys Leu Le - #u Ile Ser Cys Tyr Val     #   185     - AAA GCA GAA ACT CAA AGT ATA AAA GAT ACA AA - #A GAA GCT ATA TCA TCT     2245     Lys Ala Glu Thr Gln Ser Ile Lys Asp Thr Ly - #s Glu Ala Ile Ser Ser     190                 1 - #95                 2 - #00                 2 -     #05     - GAA GTG GAC ACT CAA AGT ACA GAA GAT TCA GA - #A TTA GAA ACT ATC TCA     2293     Glu Val Asp Thr Gln Ser Thr Glu Asp Ser Gl - #u Leu Glu Thr Ile Ser     #               220     - GTC ACT GCA GAA AAA ATA AGA GAT CGT AAA GA - #T AAT GAA GTA ACT GGA     2341     Val Thr Ala Glu Lys Ile Arg Asp Arg Lys As - #p Asn Glu Val Thr Gly     #           235     - CTT GGC AAA ATT ATA AAA ACG AGT GAA AGT AT - #C AGC CGA GAA CAA GTA     2389     Leu Gly Lys Ile Ile Lys Thr Ser Glu Ser Il - #e Ser Arg Glu Gln Val     #       250     - TTA AAT ATT CGT GAT CTA ACA CGC TAT GAT CC - #A GGC ATT TCA GTT GTA     2437     Leu Asn Ile Arg Asp Leu Thr Arg Tyr Asp Pr - #o Gly Ile Ser Val Val     #   265     - GAA CAA GGT CGC GGT GCA AGT TCT GGA TAT TC - #T ATT CGT GGT ATG GAC     2485     Glu Gln Gly Arg Gly Ala Ser Ser Gly Tyr Se - #r Ile Arg Gly Met Asp     270                 2 - #75                 2 - #80                 2 -     #85     - AGA AAT AGA GTT GCT TTA TTA GTA GAT GGT TT - #A CCT CAA ACG CAA TCT     2533     Arg Asn Arg Val Ala Leu Leu Val Asp Gly Le - #u Pro Gln Thr Gln Ser     #               300     - TAT GTA GTG CAA AGC CCT TTA GTT GCT CGT TC - #A GGA TAT TCT GGC ACT     2581     Tyr Val Val Gln Ser Pro Leu Val Ala Arg Se - #r Gly Tyr Ser Gly Thr     #           315     - GGT GCA ATT AAT GAA ATT GAA TAT GAA AAT GT - #A AAG GCC GTC GAA ATA     2629     Gly Ala Ile Asn Glu Ile Glu Tyr Glu Asn Va - #l Lys Ala Val Glu Ile     #       330     - AGC AAG GGG GGG AGT TCT TCT GAG TAT GGT AA - #T GGA GCA CTA GCT GGT     2677     Ser Lys Gly Gly Ser Ser Ser Glu Tyr Gly As - #n Gly Ala Leu Ala Gly     #   345     - TCT GTA ACA TTT CAA AGC AAA TCC GCA GCC GA - #T ATC TTA GAA GGA GAC     2725     Ser Val Thr Phe Gln Ser Lys Ser Ala Ala As - #p Ile Leu Glu Gly Asp     350                 3 - #55                 3 - #60                 3 -     #65     - AAA TCA TGG GGA ATT CAA ACT AAA AAT GCT TA - #T TCA AGC AAA AAT AAA     2773     Lys Ser Trp Gly Ile Gln Thr Lys Asn Ala Ty - #r Ser Ser Lys Asn Lys     #               380     - GGC TTT ACC CAT TCT TTA GCT GTA GCA GGA AA - #A CAA GGT GGA TTT GAA     2821     Gly Phe Thr His Ser Leu Ala Val Ala Gly Ly - #s Gln Gly Gly Phe Glu     #           395     - GGG GTC GCC ATT TAC ACT CAA CGA AAT TCG GA - #G GAA ACC CAA GTC CAT     2869     Gly Val Ala Ile Tyr Thr Gln Arg Asn Ser Gl - #u Glu Thr Gln Val His     #       410     - AAA GAT GCA TTA AAA GGC GTA CAA AGT TAT GA - #G CGA TTC ATC GCC ACA     2917     Lys Asp Ala Leu Lys Gly Val Gln Ser Tyr Gl - #u Arg Phe Ile Ala Thr     #   425     - ACA GAT AAA TCT TCA GGA TAC TTT GTG ATA CA - #A GGT GAG TGT CCA AAT     2965     Thr Asp Lys Ser Ser Gly Tyr Phe Val Ile Gl - #n Gly Glu Cys Pro Asn     430                 4 - #35                 4 - #40                 4 -     #45     - GGT GAT GAC AAG TGT GCA GCC AAA CCA CCT GC - #A AAG TTA TCC CCC CAA     3013     Gly Asp Asp Lys Cys Ala Ala Lys Pro Pro Al - #a Lys Leu Ser Pro Gln     #               460     - AGC GAA ACC GTA AGC GTT TCA GAT TAT ACG GG - #G GCT AAC CGT ATC AAA     3061     Ser Glu Thr Val Ser Val Ser Asp Tyr Thr Gl - #y Ala Asn Arg Ile Lys     #           475     - CCT AAT CCA ATG AAA TAT GAA AGC CAG TCT TG - #G TTT TTA AGA GGA GGG     3109     Pro Asn Pro Met Lys Tyr Glu Ser Gln Ser Tr - #p Phe Leu Arg Gly Gly     #       490     - TAT CAT TTT TCT GAA CAA CAC TAT ATT GGT GG - #T ATT TTT GAA TTC ACA     3157     Tyr His Phe Ser Glu Gln His Tyr Ile Gly Gl - #y Ile Phe Glu Phe Thr     #   505     - CAA CAA AAA TTT GAT ATC CGT GAT ATG ACA TT - #T CCC GCT TAT TTA AGA     3205     Gln Gln Lys Phe Asp Ile Arg Asp Met Thr Ph - #e Pro Ala Tyr Leu Arg     510                 5 - #15                 5 - #20                 5 -     #25     - TCA ACA GAA AAA CGG GAT GAT AGA ACT GGC CC - #T TTT TAT CCA AAG CAA     3253     Ser Thr Glu Lys Arg Asp Asp Arg Thr Gly Pr - #o Phe Tyr Pro Lys Gln     #               540     - GAT TAT GGT GCA TAT CAA CGT ATT GAG GAT GG - #C CGA GGC GTT AAC TAT     3301     Asp Tyr Gly Ala Tyr Gln Arg Ile Glu Asp Gl - #y Arg Gly Val Asn Tyr     #           555     - GCA AGT GGG CTT TAT TTC GAT GAA CAC CAT AG - #A AAA CAG CGT GTA GGT     3349     Ala Ser Gly Leu Tyr Phe Asp Glu His His Ar - #g Lys Gln Arg Val Gly     #       570     - ATT GAA TAT ATT TAC GAA AAT AAG AAC AAA GC - #G GGC ATC ATT GAC AAA     3397     Ile Glu Tyr Ile Tyr Glu Asn Lys Asn Lys Al - #a Gly Ile Ile Asp Lys     #   585     - GCA GTG TTA AGT GCT AAT CAA CAA AAC ATC AT - #A CTT GAC AGT TAT ATG     3445     Ala Val Leu Ser Ala Asn Gln Gln Asn Ile Il - #e Leu Asp Ser Tyr Met     590                 5 - #95                 6 - #00                 6 -     #05     - CGA CAT ACG CAT TGC AGT CTT TAT CCT AAT CC - #A AGT AAG AAT TGC CGC     3493     Arg His Thr His Cys Ser Leu Tyr Pro Asn Pr - #o Ser Lys Asn Cys Arg     #               620     - CCG ACA CTT GAT AAA CCT TAT TCA TAC TAT CG - #T TCT GAT AGA AAT GTT     3541     Pro Thr Leu Asp Lys Pro Tyr Ser Tyr Tyr Ar - #g Ser Asp Arg Asn Val     #           635     - TAT AAA GAA AAA CAT AAT ATG TTG CAA TTG AA - #T TTA GAG AAA AAA ATT     3589     Tyr Lys Glu Lys His Asn Met Leu Gln Leu As - #n Leu Glu Lys Lys Ile     #       650     - CAA CAA AAT TGG CTT ACT CAT CAA ATT GTC TT - #C AAT CTT GGT TTT GAT     3637     Gln Gln Asn Trp Leu Thr His Gln Ile Val Ph - #e Asn Leu Gly Phe Asp     #   665     - GAC TTT ACT TCA GCG CTT CAG CAT AAA GAT TA - #T TTA ACT CGA CGT GTT     3685     Asp Phe Thr Ser Ala Leu Gln His Lys Asp Ty - #r Leu Thr Arg Arg Val     670                 6 - #75                 6 - #80                 6 -     #85     - ACC GCT ACG GCA AAT ATT ATT TCA GGG ACA GT - #T GCT GGT AAA CGA AGA     3733     Thr Ala Thr Ala Asn Ile Ile Ser Gly Thr Va - #l Ala Gly Lys Arg Arg     #               700     - AAT GGT TAC GAA AAA CAA CCT TAC TTA TAC TC - #A AAA CCA AAA GTA GAT     3781     Asn Gly Tyr Glu Lys Gln Pro Tyr Leu Tyr Se - #r Lys Pro Lys Val Asp     #           715     - TTT GTA GGA CAA GAT CAT TGT AAT TAT AAA GG - #T AGC TCC TCT AAT TAC     3829     Phe Val Gly Gln Asp His Cys Asn Tyr Lys Gl - #y Ser Ser Ser Asn Tyr     #       730     - AGC GAC TGT AAA GTG CGG TTA ATT AAA GGG AA - #A AAT TAT TAT TTC GCA     3877     Ser Asp Cys Lys Val Arg Leu Ile Lys Gly Ly - #s Asn Tyr Tyr Phe Ala     #   745     - GCA CGC AAT AAT ATG GCA TTA GGG AAA TAC AT - #T GAT TTA GGT TTA GGT     3925     Ala Arg Asn Asn Met Ala Leu Gly Lys Tyr Il - #e Asp Leu Gly Leu Gly     750                 7 - #55                 7 - #60                 7 -     #65     - ATT CGG TAT GAC GTA TCT CGT ACA AAA GCT AA - #T GAA TCA ACT ATT AGT     3973     Ile Arg Tyr Asp Val Ser Arg Thr Lys Ala As - #n Glu Ser Thr Ile Ser     #               780     - GTT GGT AAA TTT AAA AAT TTC TCT TGG AAT AC - #T GGT ATT GTC ATA AAA     4021     Val Gly Lys Phe Lys Asn Phe Ser Trp Asn Th - #r Gly Ile Val Ile Lys     #           795     - CCA ACG GAA TGG CTT GAT CTT TCT TAT CGC CT - #T TCT ACT GGA TTT AGA     4069     Pro Thr Glu Trp Leu Asp Leu Ser Tyr Arg Le - #u Ser Thr Gly Phe Arg     #       810     - AAT CCT AGT TTT GCT GAA ATG TAT GGT TGG CG - #G TAT GGT GGC AAT AAT     4117     Asn Pro Ser Phe Ala Glu Met Tyr Gly Trp Ar - #g Tyr Gly Gly Asn Asn     #   825     - AGC GAT GTT TAT GTA GGT AAA TTT AAG CCT GA - #A ACA TCT CGT AAC CAA     4165     Ser Asp Val Tyr Val Gly Lys Phe Lys Pro Gl - #u Thr Ser Arg Asn Gln     830                 8 - #35                 8 - #40                 8 -     #45     - GAG TTT GGT CTC GCT CTA AAA GGG GAT TTT GG - #T AAT ATT GAG ATC AGT     4213     Glu Phe Gly Leu Ala Leu Lys Gly Asp Phe Gl - #y Asn Ile Glu Ile Ser     #               860     - CAT TTT AGT AAT GCT TAT CGA AAT CTT ATC GC - #C TTT GCT GAA GAA CTT     4261     His Phe Ser Asn Ala Tyr Arg Asn Leu Ile Al - #a Phe Ala Glu Glu Leu     #           875     - AGT AAA AAT GGA ACT ACT GGA AAG GGC AAT TA - #T GGA TAT CAT AAT GCA     4309     Ser Lys Asn Gly Thr Thr Gly Lys Gly Asn Ty - #r Gly Tyr His Asn Ala     #       890     - CAA AAT GCA AAA TTA GTT GGC GTA AAT ATA AC - #T GCG CAA TTA GAT TTT     4357     Gln Asn Ala Lys Leu Val Gly Val Asn Ile Th - #r Ala Gln Leu Asp Phe     #   905     - AAT GGT TTA TGG AAA CGT ATT CCC TAC GGT TG - #G TAT GCA ACA TTT GCT     4405     Asn Gly Leu Trp Lys Arg Ile Pro Tyr Gly Tr - #p Tyr Ala Thr Phe Ala     910                 9 - #15                 9 - #20                 9 -     #25     - TAT AAC CGA GTA AAA GTT AAA GAT CAA AAA AT - #C AAT GCT GGT TTG GCC     4453     Tyr Asn Arg Val Lys Val Lys Asp Gln Lys Il - #e Asn Ala Gly Leu Ala     #               940     - TCC GTA AGC AGT TAT TTA TTT GAT GCC ATT CA - #G CCC AGC CGT TAT ATC     4501     Ser Val Ser Ser Tyr Leu Phe Asp Ala Ile Gl - #n Pro Ser Arg Tyr Ile     #           955     - ATT GGT TTA GGC TAT GAT CAT CCA AGT AAT AC - #T TGG GGA ATT AAT ACA     4549     Ile Gly Leu Gly Tyr Asp His Pro Ser Asn Th - #r Trp Gly Ile Asn Thr     #       970     - ATG TTT ACT CAA TCA AAA GCA AAA TCT CAA AA - #T GAA TTG CTA GGA CAA     4597     Met Phe Thr Gln Ser Lys Ala Lys Ser Gln As - #n Glu Leu Leu Gly Gln     #   985     - CGT GCA TTG GGT AAC AAT TCA AGG AAT GTA AA - #A TCA ACA AGA AAA CTT     4645     Arg Ala Leu Gly Asn Asn Ser Arg Asn Val Ly - #s Ser Thr Arg Lys Leu     990                 9 - #95                 1 - #000                1005     - ACT CGG GCA TGG CAT ATC TTA GAT GTA TCG GG - #T TAT TAC ATG GCG AAT     4693     Thr Arg Ala Trp His Ile Leu Asp Val Ser Gl - #y Tyr Tyr Met Ala Asn     #              10205     - AAA AAT ATT ATG CTT CGA TTA GGG ATA TAT AA - #T TTA TTC AAC TAT CGC     4741     Lys Asn Ile Met Leu Arg Leu Gly Ile Tyr As - #n Leu Phe Asn Tyr Arg     #          10350     - TAT GTT ACT TGG GAA GCG GTG CGT CAA ACA GC - #A CAA GGT GCG GTC AAT     4789     Tyr Val Thr Trp Glu Ala Val Arg Gln Thr Al - #a Gln Gly Ala Val Asn     #      10505     - CAA CAT CAA AAT GTT GGT AGC TAT ACT CGC TA - #C GCA GCA TCA GGA CGA     4837     Gln His Gln Asn Val Gly Ser Tyr Thr Arg Ty - #r Ala Ala Ser Gly Arg     #  10650     - AAC TAT ACC TTA ACA TTA GAA ATG AAA TTC TA - #AATTAAAA TGCGCCAGAT     4887     Asn Tyr Thr Leu Thr Leu Glu Met Lys Phe     1070                1075     - GGACTAGATA TGCTATATCT ATACCTTACT GGCGCATCTT TTTCTGTTCT AT - #AATCTGCT     4947     - TAAGTGAAAA ACCAAACTTG GATTTTTTAC AAGATCTTTT CACGCATTTA TT - #GTAAAATC     5007     - TCCGACAATT TTTACCGCAC TTTTCTCTAT TACAAAAACA ATAAGGATCC TT - #TTGTGACT     5067     - CTCTCAATCT TTGGCAAGTT GCTGTTACAA CTTCAGATCA AGTTTCAGCC AG - #CGATCTTA     5127     # 5144             C     - (2) INFORMATION FOR SEQ ID NO: 106:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 168 amino               (B) TYPE: amino acid               (D) TOPOLOGY: linear     #ID NO: 106:i) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu Leu     Ser     #   15     -      Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser Asn     Pro     #                 30     -      Ser Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Asn Gln Arg     Thr     #             45     -      Lys Ser Asp Leu Gln Lys Leu Ser - # Ile Pro Ser Leu Gly Gly Gly     Met     #         60     -      Lys Leu Val Ala Gln Asn Leu Leu - # Gly Lys Lys Glu Pro Ser Leu     Leu     #     80     -      Asn Asn Glu Asp Gly Tyr Met Ile - # Phe Ser Ser Leu Ser Thr Ile     Glu     #   95     -      Glu Asp Val Thr Lys Glu Asn Lys - # Ser Gln Glu Pro Thr Ile Gly     Ser     #                110     -      Ile Asp Glu Pro Ser Lys Thr Asn - # Ser Pro Gln Asn His His Gly     Asn     #            125     -      Met Tyr Ile Arg Val Phe Ile Ile - # Phe Asn Arg Gly Val Ile Pro     Gln     #        140     -      Met Ala Ser Phe Ile Gln Val Thr - # Met Asp Met Arg Ile Thr Leu     Ala     #    160     -      Ser Lys Gln Pro Leu His Tyr Leu     #   165     - (2) INFORMATION FOR SEQ ID NO: 107:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 911 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 107:i) SEQUENCE DESCRIPTION: SEQ     -      Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys Leu     Leu     #   15     -      Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp Thr     Lys     #                 30     -      Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp Ser     Glu     #             45     -      Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Ile Arg Asp Arg Lys     Asp     #         60     -      Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu Ser     Ile     #     80     -      Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr Asp     Pro     #   95     -      Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly Tyr     Ser     #                110     -      Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp Gly     Leu     #            125     -      Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala Arg     Ser     #        140     -      Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu Asn     Val     #    160     -      Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr Gly     Asn     #   175     -      Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala Ala     Asp     #                190     -      Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn Ala     Tyr     #            205     -      Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala Gly     Lys     #        220     -      Gln Gly Gly Phe Glu Gly Val Ala - # Ile Tyr Thr Gln Arg Asn Ser     Glu     #    240     -      Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser Tyr     Glu     #   255     -      Arg Phe Ile Ala Thr Thr Asp Lys - # Ser Ser Gly Tyr Phe Val Ile     Gln     #                270     -      Gly Glu Cys Pro Asn Gly Asp Asp - # Lys Cys Ala Ala Lys Pro Pro     Ala     #            285     -      Lys Leu Ser Pro Gln Ser Glu Thr - # Val Ser Val Ser Asp Tyr Thr     Gly     #        300     -      Ala Asn Arg Ile Lys Pro Asn Pro - # Met Lys Tyr Glu Ser Gln Ser     Trp     #    320     -      Phe Leu Arg Gly Gly Tyr His Phe - # Ser Glu Gln His Tyr Ile Gly     Gly     #   335     -      Ile Phe Glu Phe Thr Gln Gln Lys - # Phe Asp Ile Arg Asp Met Thr     Phe     #                350     -      Pro Ala Tyr Leu Arg Ser Thr Glu - # Lys Arg Asp Asp Arg Thr Gly     Pro     #            365     -      Phe Tyr Pro Lys Gln Asp Tyr Gly - # Ala Tyr Gln Arg Ile Glu Asp     Gly     #        380     -      Arg Gly Val Asn Tyr Ala Ser Gly - # Leu Tyr Phe Asp Glu His His     Arg     #    400     -      Lys Gln Arg Val Gly Ile Glu Tyr - # Ile Tyr Glu Asn Lys Asn Lys     Ala     #   415     -      Gly Ile Ile Asp Lys Ala Val Leu - # Ser Ala Asn Gln Gln Asn Ile     Ile     #                430     -      Leu Asp Ser Tyr Met Arg His Thr - # His Cys Ser Leu Tyr Pro Asn     Pro     #            445     -      Ser Lys Asn Cys Arg Pro Thr Leu - # Asp Lys Pro Tyr Ser Tyr Tyr     Arg     #        460     -      Ser Asp Arg Asn Val Tyr Lys Glu - # Lys His Asn Met Leu Gln Leu     Asn     #    480     -      Leu Glu Lys Lys Ile Gln Gln Asn - # Trp Leu Thr His Gln Ile Val     Phe     #   495     -      Asn Leu Gly Phe Asp Asp Phe Thr - # Ser Ala Leu Gln His Lys Asp     Tyr     #                510     -      Leu Thr Arg Arg Val Thr Ala Thr - # Ala Asn Ile Ile Ser Gly Thr     Val     #            525     -      Ala Gly Lys Arg Arg Asn Gly Tyr - # Glu Lys Gln Pro Tyr Leu Tyr     Ser     #        540     -      Lys Pro Lys Val Asp Phe Val Gly - # Gln Asp His Cys Asn Tyr Lys     Gly     #    560     -      Ser Ser Ser Asn Tyr Ser Asp Cys - # Lys Val Arg Leu Ile Lys Gly     Lys     #   575     -      Asn Tyr Tyr Phe Ala Ala Arg Asn - # Asn Met Ala Leu Gly Lys Tyr     Ile     #                590     -      Asp Leu Gly Leu Gly Ile Arg Tyr - # Asp Val Ser Arg Thr Lys Ala     Asn     #            605     -      Glu Ser Thr Ile Ser Val Gly Lys - # Phe Lys Asn Phe Ser Trp Asn     Thr     #        620     -      Gly Ile Val Ile Lys Pro Thr Glu - # Trp Leu Asp Leu Ser Tyr Arg     Leu     #    640     -      Ser Thr Gly Phe Arg Asn Pro Ser - # Phe Ala Glu Met Tyr Gly Trp     Arg     #   655     -      Tyr Gly Gly Asn Asn Ser Asp Val - # Tyr Val Gly Lys Phe Lys Pro     Glu     #                670     -      Thr Ser Arg Asn Gln Glu Phe Gly - # Leu Ala Leu Lys Gly Asp Phe     Gly     #            685     -      Asn Ile Glu Ile Ser His Phe Ser - # Asn Ala Tyr Arg Asn Leu Ile     Ala     #        700     -      Phe Ala Glu Glu Leu Ser Lys Asn - # Gly Thr Thr Gly Lys Gly Asn     Tyr     #    720     -      Gly Tyr His Asn Ala Gln Asn Ala - # Lys Leu Val Gly Val Asn Ile     Thr     #   735     -      Ala Gln Leu Asp Phe Asn Gly Leu - # Trp Lys Arg Ile Pro Tyr Gly     Trp     #                750     -      Tyr Ala Thr Phe Ala Tyr Asn Arg - # Val Lys Val Lys Asp Gln Lys     Ile     #            765     -      Asn Ala Gly Leu Ala Ser Val Ser - # Ser Tyr Leu Phe Asp Ala Ile     Gln     #        780     -      Pro Ser Arg Tyr Ile Ile Gly Leu - # Gly Tyr Asp His Pro Ser Asn     Thr     #    800     -      Trp Gly Ile Asn Thr Met Phe Thr - # Gln Ser Lys Ala Lys Ser Gln     Asn     #   815     -      Glu Leu Leu Gly Gln Arg Ala Leu - # Gly Asn Asn Ser Arg Asn Val     Lys     #                830     -      Ser Thr Arg Lys Leu Thr Arg Ala - # Trp His Ile Leu Asp Val Ser     Gly     #            845     -      Tyr Tyr Met Ala Asn Lys Asn Ile - # Met Leu Arg Leu Gly Ile Tyr     Asn     #        860     -      Leu Phe Asn Tyr Arg Tyr Val Thr - # Trp Glu Ala Val Arg Gln Thr     Ala     #    880     -      Gln Gly Ala Val Asn Gln His Gln - # Asn Val Gly Ser Tyr Thr Arg     Tyr     #   895     -      Ala Ala Ser Gly Arg Asn Tyr Thr - # Leu Thr Leu Glu Met Lys Phe     #                910     - (2) INFORMATION FOR SEQ ID NO: 108:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 1993 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     -     (ix) FEATURE:               (A) NAME/KEY: CDS               (B) LOCATION: 3..1946     #ID NO: 108:i) SEQUENCE DESCRIPTION: SEQ     - AT ATG AAA TCT GTA CCT CTT ATC TCT GGT GGA - # CTT TCC TTT TTA TTA       47     #Gly Leu Ser Phe Leu Leueu Ile Ser Gly     #  15     - AGT GCT TGT AGC GGG GGA GGT GGT TCT TTT GA - #T GTA GAT GAC GTC TCT       95     Ser Ala Cys Ser Gly Gly Gly Gly Ser Phe As - #p Val Asp Asp Val Ser     #                 30     - AAT CCC TCC TCT TCT AAA CCA CGT TAT CAA GA - #C GAT ACT TCA AGT TCA      143     Asn Pro Ser Ser Ser Lys Pro Arg Tyr Gln As - #p Asp Thr Ser Ser Ser     #             45     - AGA ACA AAA TCT AAA TTG GAA AAT TTG TCC AT - #T CCT TCT TTA GGG GGA      191     Arg Thr Lys Ser Lys Leu Glu Asn Leu Ser Il - #e Pro Ser Leu Gly Gly     #         60     - GGG ATG AAG TTA GTG GCT CAG AAT CTT CGT GA - #T AGG ACA AAA CCT AGT      239     Gly Met Lys Leu Val Ala Gln Asn Leu Arg As - #p Arg Thr Lys Pro Ser     #     75     - CTC TTA AAT GAA GAT GAC TAT ATG ATA TTT TC - #C TCA CTT TCA ACG ATT      287     Leu Leu Asn Glu Asp Asp Tyr Met Ile Phe Se - #r Ser Leu Ser Thr Ile     # 95     - AAA GCT GAT GTT GAA AAA GAA AAT AAA CAC TA - #T ACA AGT CCA GTT GGC      335     Lys Ala Asp Val Glu Lys Glu Asn Lys His Ty - #r Thr Ser Pro Val Gly     #               110     - TCA ATA GAC GAG CCT AGT ACA ACA AAT CCA AA - #A GAA AAT GAT CAT GGA      383     Ser Ile Asp Glu Pro Ser Thr Thr Asn Pro Ly - #s Glu Asn Asp His Gly     #           125     - CAA AGA TAT GTA TAT TCA GGA CTT TAT TAT AT - #T CCA TCG TGG AAT TTA      431     Gln Arg Tyr Val Tyr Ser Gly Leu Tyr Tyr Il - #e Pro Ser Trp Asn Leu     #       140     - AAC GAT CTT AAA AAT AAC AAG TAT TAT TAT TC - #T GGT TAC TAT GGA TAT      479     Asn Asp Leu Lys Asn Asn Lys Tyr Tyr Tyr Se - #r Gly Tyr Tyr Gly Tyr     #   155     - GCG TAT TAC TTT GGC AAG CAA ACA GCC ACT AC - #A TTA CCT GTA AAT GGC      527     Ala Tyr Tyr Phe Gly Lys Gln Thr Ala Thr Th - #r Leu Pro Val Asn Gly     160                 1 - #65                 1 - #70                 1 -     #75     - AAA GTA ACG TAT AAA GGA ACT TGG AGC TTC AT - #C ACC GCA GCT GAA AAT      575     Lys Val Thr Tyr Lys Gly Thr Trp Ser Phe Il - #e Thr Ala Ala Glu Asn     #               190     - GGC AAA AGG TAT CCT TTG TTA AGT AAT GGC AG - #T CAA GCT TAT TTT CGA      623     Gly Lys Arg Tyr Pro Leu Leu Ser Asn Gly Se - #r Gln Ala Tyr Phe Arg     #           205     - CGT AGT GCA ATT CCA GAA GAT ATT GAT TTA GA - #A GTT AAA AAT GAT GAG      671     Arg Ser Ala Ile Pro Glu Asp Ile Asp Leu Gl - #u Val Lys Asn Asp Glu     #       220     - AAT AGA GAA AAA GGG CTA GTG AGT GAA TTT AG - #T GCA GAT TTT GGG ACT      719     Asn Arg Glu Lys Gly Leu Val Ser Glu Phe Se - #r Ala Asp Phe Gly Thr     #   235     - AAA AAA CTG ACA GGA GGA CTG TTT TAC ACC AA - #A AGA CAA ACT CAT ATT      767     Lys Lys Leu Thr Gly Gly Leu Phe Tyr Thr Ly - #s Arg Gln Thr His Ile     240                 2 - #45                 2 - #50                 2 -     #55     - CAA AAC CAT GAA AAG AAA AAA CTC TAT GAT AT - #A GAT GCC CAT ATT TAT      815     Gln Asn His Glu Lys Lys Lys Leu Tyr Asp Il - #e Asp Ala His Ile Tyr     #               270     - AGT AAT AGA TTC AGA GGT AAA GTA AAT CCT AC - #C CAA AAA GAT TCT AAA      863     Ser Asn Arg Phe Arg Gly Lys Val Asn Pro Th - #r Gln Lys Asp Ser Lys     #           285     - GAA CAT CCC TTT ACC AGC GAG GGA ACA TTA GA - #A GGT GGT TTT TAC GGG      911     Glu His Pro Phe Thr Ser Glu Gly Thr Leu Gl - #u Gly Gly Phe Tyr Gly     #       300     - CCT GAA GGT CAA GAA TTA GGA GGA AAG TTT TT - #A GCT GGC GAC AAA AAA      959     Pro Glu Gly Gln Glu Leu Gly Gly Lys Phe Le - #u Ala Gly Asp Lys Lys     #   315     - GTT TTT GGG GTA TTT AGT GCC AAA GGA ACG GA - #A GAA AAC AAA AAA TTA     1007     Val Phe Gly Val Phe Ser Ala Lys Gly Thr Gl - #u Glu Asn Lys Lys Leu     320                 3 - #25                 3 - #30                 3 -     #35     - CCC AAA GAA ACC TTA ATT GAT GGC AAG CTA AC - #T ACT TTC TCT ACT AAA     1055     Pro Lys Glu Thr Leu Ile Asp Gly Lys Leu Th - #r Thr Phe Ser Thr Lys     #               350     - ACA ACC GAT GCA AAA ACC AAT GCA ACA GCC AA - #T GCA ACA ACC AGT ACC     1103     Thr Thr Asp Ala Lys Thr Asn Ala Thr Ala As - #n Ala Thr Thr Ser Thr     #           365     - GCA GCC AAT ACA ACA ACC GAT ACA ACA GCC AA - #T ACA ATA ACC GAT GCA     1151     Ala Ala Asn Thr Thr Thr Asp Thr Thr Ala As - #n Thr Ile Thr Asp Ala     #       380     - GAA AAC TTT AAG ACG AAA GAT ATA TCA AGT TT - #T GGT GAA GCT GAT TAC     1199     Glu Asn Phe Lys Thr Lys Asp Ile Ser Ser Ph - #e Gly Glu Ala Asp Tyr     #   395     - CTT TTA ATT GAT AAT TAC CCT GTT CCT CTT TT - #A CCT GAG AGT GGT GAT     1247     Leu Leu Ile Asp Asn Tyr Pro Val Pro Leu Le - #u Pro Glu Ser Gly Asp     400                 4 - #05                 4 - #10                 4 -     #15     - TTC ATA AGT AGT AAG CAC CAT ACT GTA GGA AA - #G AAA ACC TAT CAA GTA     1295     Phe Ile Ser Ser Lys His His Thr Val Gly Ly - #s Lys Thr Tyr Gln Val     #               430     - AAA GCA TGT TGC AGT AAT CTA AGC TAT GTG AA - #A TTT GGT ATG TAT TAT     1343     Lys Ala Cys Cys Ser Asn Leu Ser Tyr Val Ly - #s Phe Gly Met Tyr Tyr     #           445     - GAA GTC CCA CCT AAA GAA GAA GAA AAA GAC AA - #A GAA AAA AAA GAA AAA     1391     Glu Val Pro Pro Lys Glu Glu Glu Lys Asp Ly - #s Glu Lys Lys Glu Lys     #       460     - GAA AAA GAA AAA CAA GCG ACA AAT CTA TCG AA - #C ACT TAT TAT CAA TTC     1439     Glu Lys Glu Lys Gln Ala Thr Asn Leu Ser As - #n Thr Tyr Tyr Gln Phe     #   475     - TTA TTA GGT CTC CGT ACT CCC AGT TCT GAA AT - #T CCT AAA GGA GGA AGT     1487     Leu Leu Gly Leu Arg Thr Pro Ser Ser Glu Il - #e Pro Lys Gly Gly Ser     480                 4 - #85                 4 - #90                 4 -     #95     - GCA AAA TAT CTC GGT AGT TGG TTT GGT TAT CT - #G AGC GAT GGT TCA ACA     1535     Ala Lys Tyr Leu Gly Ser Trp Phe Gly Tyr Le - #u Ser Asp Gly Ser Thr     #               510     - TCT TAC TCC CCC AGT GGT GAT AAG AAA CGC GA - #G AAC AAT GCT CTC GCC     1583     Ser Tyr Ser Pro Ser Gly Asp Lys Lys Arg Gl - #u Asn Asn Ala Leu Ala     #           525     - GAG TTT AAT GTA AAT TTT GTC GAT AAA ACA TT - #A AAA GGC CAA TTA ATA     1631     Glu Phe Asn Val Asn Phe Val Asp Lys Thr Le - #u Lys Gly Gln Leu Ile     #       540     - CGA CAC GAT AAT CAA AAT ACC GTT TTT ACA AT - #T GAT GCA ACC TTT AAA     1679     Arg His Asp Asn Gln Asn Thr Val Phe Thr Il - #e Asp Ala Thr Phe Lys     #   555     - GGT GGT AAG AAT AAC TTC ACT GGT ACA GCA AC - #C GCA AAC AAT GTA GCG     1727     Gly Gly Lys Asn Asn Phe Thr Gly Thr Ala Th - #r Ala Asn Asn Val Ala     560                 5 - #65                 5 - #70                 5 -     #75     - ATT GAT CCC CAA AGT ACA CAA GGC ACA TCT AA - #C GTC AAT TTC ACG GCA     1775     Ile Asp Pro Gln Ser Thr Gln Gly Thr Ser As - #n Val Asn Phe Thr Ala     #               590     - ACA GTA AAT GGG GCA TTT TAT GGG CCG AAC GC - #T ACA GAA TTA GGC GGT     1823     Thr Val Asn Gly Ala Phe Tyr Gly Pro Asn Al - #a Thr Glu Leu Gly Gly     #           605     - TAT TTC ACC TAT AAC GGA AAT CCT ACA GAT AA - #A AGT TCC TCA ACC GTA     1871     Tyr Phe Thr Tyr Asn Gly Asn Pro Thr Asp Ly - #s Ser Ser Ser Thr Val     #       620     - CCT TCA TCA TCC AAT TCA AAA AAT GCA AGA GC - #T GCA GTT GTC TTT GGT     1919     Pro Ser Ser Ser Asn Ser Lys Asn Ala Arg Al - #a Ala Val Val Phe Gly     #   635     - GCG AGA CAA CAA GTA GAA ACA ACC AAA TAATGGAAT - #A CTAAAAATGA     1966     Ala Arg Gln Gln Val Glu Thr Thr Lys     640                 6 - #45     #           1993   AAGC CGAATTC     - (2) INFORMATION FOR SEQ ID NO: 109:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 648 amino               (B) TYPE: amino acid               (D) TOPOLOGY: linear     -     (ii) MOLECULE TYPE: protein     #ID NO: 109:i) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu Leu     Ser     #   15     -      Ala Cys Ser Gly Gly Gly Gly Ser - # Phe Asp Val Asp Asp Val Ser     Asn     #                 30     -      Pro Ser Ser Ser Lys Pro Arg Tyr - # Gln Asp Asp Thr Ser Ser Ser     Arg     #             45     -      Thr Lys Ser Lys Leu Glu Asn Leu - # Ser Ile Pro Ser Leu Gly Gly     Gly     #         60     -      Met Lys Leu Val Ala Gln Asn Leu - # Arg Asp Arg Thr Lys Pro Ser     Leu     #     80     -      Leu Asn Glu Asp Asp Tyr Met Ile - # Phe Ser Ser Leu Ser Thr Ile     Lys     #   95     -      Ala Asp Val Glu Lys Glu Asn Lys - # His Tyr Thr Ser Pro Val Gly     Ser     #                110     -      Ile Asp Glu Pro Ser Thr Thr Asn - # Pro Lys Glu Asn Asp His Gly     Gln     #            125     -      Arg Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Ile Pro Ser Trp Asn Leu     Asn     #        140     -      Asp Leu Lys Asn Asn Lys Tyr Tyr - # Tyr Ser Gly Tyr Tyr Gly Tyr     Ala     #    160     -      Tyr Tyr Phe Gly Lys Gln Thr Ala - # Thr Thr Leu Pro Val Asn Gly     Lys     #   175     -      Val Thr Tyr Lys Gly Thr Trp Ser - # Phe Ile Thr Ala Ala Glu Asn     Gly     #                190     -      Lys Arg Tyr Pro Leu Leu Ser Asn - # Gly Ser Gln Ala Tyr Phe Arg     Arg     #            205     -      Ser Ala Ile Pro Glu Asp Ile Asp - # Leu Glu Val Lys Asn Asp Glu     Asn     #        220     -      Arg Glu Lys Gly Leu Val Ser Glu - # Phe Ser Ala Asp Phe Gly Thr     Lys     #    240     -      Lys Leu Thr Gly Gly Leu Phe Tyr - # Thr Lys Arg Gln Thr His Ile     Gln     #   255     -      Asn His Glu Lys Lys Lys Leu Tyr - # Asp Ile Asp Ala His Ile Tyr     Ser     #                270     -      Asn Arg Phe Arg Gly Lys Val Asn - # Pro Thr Gln Lys Asp Ser Lys     Glu     #            285     -      His Pro Phe Thr Ser Glu Gly Thr - # Leu Glu Gly Gly Phe Tyr Gly     Pro     #        300     -      Glu Gly Gln Glu Leu Gly Gly Lys - # Phe Leu Ala Gly Asp Lys Lys     Val     #    320     -      Phe Gly Val Phe Ser Ala Lys Gly - # Thr Glu Glu Asn Lys Lys Leu     Pro     #   335     -      Lys Glu Thr Leu Ile Asp Gly Lys - # Leu Thr Thr Phe Ser Thr Lys     Thr     #                350     -      Thr Asp Ala Lys Thr Asn Ala Thr - # Ala Asn Ala Thr Thr Ser Thr     Ala     #            365     -      Ala Asn Thr Thr Thr Asp Thr Thr - # Ala Asn Thr Ile Thr Asp Ala     Glu     #        380     -      Asn Phe Lys Thr Lys Asp Ile Ser - # Ser Phe Gly Glu Ala Asp Tyr     Leu     #    400     -      Leu Ile Asp Asn Tyr Pro Val Pro - # Leu Leu Pro Glu Ser Gly Asp     Phe     #   415     -      Ile Ser Ser Lys His His Thr Val - # Gly Lys Lys Thr Tyr Gln Val     Lys     #                430     -      Ala Cys Cys Ser Asn Leu Ser Tyr - # Val Lys Phe Gly Met Tyr Tyr     Glu     #            445     -      Val Pro Pro Lys Glu Glu Glu Lys - # Asp Lys Glu Lys Lys Glu Lys     Glu     #        460     -      Lys Glu Lys Gln Ala Thr Asn Leu - # Ser Asn Thr Tyr Tyr Gln Phe     Leu     #    480     -      Leu Gly Leu Arg Thr Pro Ser Ser - # Glu Ile Pro Lys Gly Gly Ser     Ala     #   495     -      Lys Tyr Leu Gly Ser Trp Phe Gly - # Tyr Leu Ser Asp Gly Ser Thr     Ser     #                510     -      Tyr Ser Pro Ser Gly Asp Lys Lys - # Arg Glu Asn Asn Ala Leu Ala     Glu     #            525     -      Phe Asn Val Asn Phe Val Asp Lys - # Thr Leu Lys Gly Gln Leu Ile     Arg     #        540     -      His Asp Asn Gln Asn Thr Val Phe - # Thr Ile Asp Ala Thr Phe Lys     Gly     #    560     -      Gly Lys Asn Asn Phe Thr Gly Thr - # Ala Thr Ala Asn Asn Val Ala     Ile     #   575     -      Asp Pro Gln Ser Thr Gln Gly Thr - # Ser Asn Val Asn Phe Thr Ala     Thr     #                590     -      Val Asn Gly Ala Phe Tyr Gly Pro - # Asn Ala Thr Glu Leu Gly Gly     Tyr     #            605     -      Phe Thr Tyr Asn Gly Asn Pro Thr - # Asp Lys Ser Ser Ser Thr Val     Pro     #        620     -      Ser Ser Ser Asn Ser Lys Asn Ala - # Arg Ala Ala Val Val Phe Gly     Ala     #    640     -      Arg Gln Gln Val Glu Thr Thr Lys     #   645     - (2) INFORMATION FOR SEQ ID NO: 110:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 1974 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     -     (ix) FEATURE:               (A) NAME/KEY: CDS               (B) LOCATION: 20..1912     #ID NO: 110:i) SEQUENCE DESCRIPTION: SEQ     - GAATTCGGCT TGGATCCAT ATG AAA TCT GTA CCT CTT ATC - # TCT GGT GGA CTT       52     #   Met Lys Ser Val Pro Leu Ile Ser Gly - # Gly Leu     #  10     - TCC TTT TTA CTA AGT GCT TGT AGC GGA GGG GG - #G TCT TTT GAT GTA GAT      100     Ser Phe Leu Leu Ser Ala Cys Ser Gly Gly Gl - #y Ser Phe Asp Val Asp     #             25     - AAC GTC TCT AAT CCA TCC TCT TCT AAA CCA CG - #T TAT CAA GAC GAT ACT      148     Asn Val Ser Asn Pro Ser Ser Ser Lys Pro Ar - #g Tyr Gln Asp Asp Thr     #         40     - TCA AGT TCA AGA ACA AAA TCT AAT TTG AAA AA - #G TTG TCC ATT CCT TCT      196     Ser Ser Ser Arg Thr Lys Ser Asn Leu Lys Ly - #s Leu Ser Ile Pro Ser     #     55     - TTA GGG GGA GGG ATG AAG TTA GTG GCT CAG AA - #T CTT AGT GAT AAG AAC      244     Leu Gly Gly Gly Met Lys Leu Val Ala Gln As - #n Leu Ser Asp Lys Asn     # 75     - AAA CCT AGT CTC TTA AAT GAA GAT GAC TAT AT - #A TCA TAT TTT TCC TCA      292     Lys Pro Ser Leu Leu Asn Glu Asp Asp Tyr Il - #e Ser Tyr Phe Ser Ser     #                 90     - CTT TCT ACA ATT CAA GAT GAT GTT AAA AAA GA - #A AAT AAA CGC CAT ACA      340     Leu Ser Thr Ile Gln Asp Asp Val Lys Lys Gl - #u Asn Lys Arg His Thr     #            105     - AAT CCA GTT GGC TCA ATA GAC GAG CCT AAC GC - #A ACA AAT CCA CCC GAA      388     Asn Pro Val Gly Ser Ile Asp Glu Pro Asn Al - #a Thr Asn Pro Pro Glu     #       120     - AAG CAT CAT GGA CAA AGA TAT GTA TAT TCA GG - #G CTT TAT TAT ATT CCA      436     Lys His His Gly Gln Arg Tyr Val Tyr Ser Gl - #y Leu Tyr Tyr Ile Pro     #   135     - TCG TGG AGT CAT TCC TCA AAT GGC AAG CTT TA - #T TTA GGT TAC TAT GGA      484     Ser Trp Ser His Ser Ser Asn Gly Lys Leu Ty - #r Leu Gly Tyr Tyr Gly     140                 1 - #45                 1 - #50                 1 -     #55     - TAT GCG TTT TAT TAT GGT AAT AAA ACT GCA AC - #A AAC TTG CCA GTA AGC      532     Tyr Ala Phe Tyr Tyr Gly Asn Lys Thr Ala Th - #r Asn Leu Pro Val Ser     #               170     - GGC ATA GCT AAA TAC AAA GGA ACT TGG GAT TT - #T ATT ACT GCA ACT AAA      580     Gly Ile Ala Lys Tyr Lys Gly Thr Trp Asp Ph - #e Ile Thr Ala Thr Lys     #           185     - AAT GGC CAA CGT TAT TCT TTA TTT GGT AGC GC - #T TTT GGA GCT TAT AAT      628     Asn Gly Gln Arg Tyr Ser Leu Phe Gly Ser Al - #a Phe Gly Ala Tyr Asn     #       200     - AGA CGC AGT GCT ATT TCA GAA GAT ATA GAT AA - #T TTA GAA AAT AAT CTA      676     Arg Arg Ser Ala Ile Ser Glu Asp Ile Asp As - #n Leu Glu Asn Asn Leu     #   215     - AAG AAT GGT GCG GGA TTA ACT AGT GAA TTT AC - #T GTC AAT TTT GGT ACG      724     Lys Asn Gly Ala Gly Leu Thr Ser Glu Phe Th - #r Val Asn Phe Gly Thr     220                 2 - #25                 2 - #30                 2 -     #35     - AAA AAG CTC ACT GGA AAA CTT TAT TAT AAT GA - #A AGG GAA ACA AAT CTT      772     Lys Lys Leu Thr Gly Lys Leu Tyr Tyr Asn Gl - #u Arg Glu Thr Asn Leu     #               250     - AAT AAA TTA CAA AAG AGA AAA CAT GAA CTC TA - #T GAT ATA GAT GCC GAT      820     Asn Lys Leu Gln Lys Arg Lys His Glu Leu Ty - #r Asp Ile Asp Ala Asp     #           265     - ATT TAT AGT AAT AGA TTC AGA GGT AAA GTA AA - #G CCA ACA ACC CAA AAA      868     Ile Tyr Ser Asn Arg Phe Arg Gly Lys Val Ly - #s Pro Thr Thr Gln Lys     #       280     - GAT TCT CAA GAA CAT CCC TTT ACC AGC GAG GG - #A ACA TTA GAA GGT GGT      916     Asp Ser Gln Glu His Pro Phe Thr Ser Glu Gl - #y Thr Leu Glu Gly Gly     #   295     - TTT TAT GGG CCT AAC GGT GAA GAA TTA GGA GG - #A AAG TTT TTA GCT GGC      964     Phe Tyr Gly Pro Asn Gly Glu Glu Leu Gly Gl - #y Lys Phe Leu Ala Gly     300                 3 - #05                 3 - #10                 3 -     #15     - GAT AAC CGA GTT TTT GGG GTA TTT AGT GCC AA - #A GAA GAA GAA ACA AAA     1012     Asp Asn Arg Val Phe Gly Val Phe Ser Ala Ly - #s Glu Glu Glu Thr Lys     #               330     - GAC AAA AAA TTA TCC AGA GAA ACC TTA ATT GA - #T GGC AAG CTA ATT ACT     1060     Asp Lys Lys Leu Ser Arg Glu Thr Leu Ile As - #p Gly Lys Leu Ile Thr     #           345     - TTT AAA AGA ACT GAT GCA ACA ACC AAT ACA GC - #A GCC AAT GCA AAA ACC     1108     Phe Lys Arg Thr Asp Ala Thr Thr Asn Thr Al - #a Ala Asn Ala Lys Thr     #       360     - GAT GAA AAA AAC TTT ACG ACG AAA GAT ATA CC - #A AGT TTT GGT GAA GCT     1156     Asp Glu Lys Asn Phe Thr Thr Lys Asp Ile Pr - #o Ser Phe Gly Glu Ala     #   375     - GAT TAC CTT TTA ATT GAT AAT TAC CCT GTT CC - #T CTT TTC CCT GAA GAA     1204     Asp Tyr Leu Leu Ile Asp Asn Tyr Pro Val Pr - #o Leu Phe Pro Glu Glu     380                 3 - #85                 3 - #90                 3 -     #95     - AAT ACT AAT GAT TTC ATA ACT AGT AGG CAC CA - #T AAG GTA GGA GAT AAA     1252     Asn Thr Asn Asp Phe Ile Thr Ser Arg His Hi - #s Lys Val Gly Asp Lys     #               410     - ACC TAT AAA GTA GAA GCA TGT TGC AAG AAT CT - #A AGC TAT GTG AAA TTT     1300     Thr Tyr Lys Val Glu Ala Cys Cys Lys Asn Le - #u Ser Tyr Val Lys Phe     #           425     - GGT ATG TAT TAT GAA GAC CCA TTA AAT GGA GA - #A AAT GGC AAA GAA AAA     1348     Gly Met Tyr Tyr Glu Asp Pro Leu Asn Gly Gl - #u Asn Gly Lys Glu Lys     #       440     - GAA AAA GAA AAA GAA AAA GAC AAA GAA AAA CA - #A GCG ACA ACA TCT ATC     1396     Glu Lys Glu Lys Glu Lys Asp Lys Glu Lys Gl - #n Ala Thr Thr Ser Ile     #   455     - AAG ACT TAT TAT CAA TTC TTA TTA GGT CAC CG - #T ACT GCC AAG GCC GAC     1444     Lys Thr Tyr Tyr Gln Phe Leu Leu Gly His Ar - #g Thr Ala Lys Ala Asp     460                 4 - #65                 4 - #70                 4 -     #75     - ATA CCT GCA ACG GGA AAC GTG AAA TAT CGC GG - #T AAT TGG TTT GGT TAT     1492     Ile Pro Ala Thr Gly Asn Val Lys Tyr Arg Gl - #y Asn Trp Phe Gly Tyr     #               490     - ATT GGT GAT GAC AAG ACA TCT TAC TCC ACT AC - #T GGA GAT AAA AAT GCT     1540     Ile Gly Asp Asp Lys Thr Ser Tyr Ser Thr Th - #r Gly Asp Lys Asn Ala     #           505     - GTC GCC GAG TTT GAT GTA AAT TTT GCC GAT AA - #A ACA TTA ACA GGC ACA     1588     Val Ala Glu Phe Asp Val Asn Phe Ala Asp Ly - #s Thr Leu Thr Gly Thr     #       520     - TTA AAA CGA CAC GAT AAT GGA AAT CCC GTA TT - #T ACA ATT AAT GCA AGC     1636     Leu Lys Arg His Asp Asn Gly Asn Pro Val Ph - #e Thr Ile Asn Ala Ser     #   535     - TTT CAA AGT GGT AAG AAT GAC TTC ACT GGT AC - #A GCA ACC GCA AAC AAT     1684     Phe Gln Ser Gly Lys Asn Asp Phe Thr Gly Th - #r Ala Thr Ala Asn Asn     540                 5 - #45                 5 - #50                 5 -     #55     - GTA GCG ATT GAT CCC CAA AAT ACA CAA ACC AC - #A TCT AGA GTC AAT TTC     1732     Val Ala Ile Asp Pro Gln Asn Thr Gln Thr Th - #r Ser Arg Val Asn Phe     #               570     - ACG GCA ACA GTA AAC GGG GCA TTT TAT GGA CC - #T AAG GCT ACA GAA TTA     1780     Thr Ala Thr Val Asn Gly Ala Phe Tyr Gly Pr - #o Lys Ala Thr Glu Leu     #           585     - GGC GGT TAT TTC ACT TAT AAC GGA AAC AAT CC - #T ACA GAT AAA AAT TCC     1828     Gly Gly Tyr Phe Thr Tyr Asn Gly Asn Asn Pr - #o Thr Asp Lys Asn Ser     #       600     - TCA ACC GTT TCA CCA TCC AAT TCA GCA AAT GC - #T CGT GCT GCC GTT GTG     1876     Ser Thr Val Ser Pro Ser Asn Ser Ala Asn Al - #a Arg Ala Ala Val Val     #   615     - TTT GGC GCT AAA AAA CAA GTA GAA ACA ACC AA - #C AAG TAAAAACAAC     1922     Phe Gly Ala Lys Lys Gln Val Glu Thr Thr As - #n Lys     620                 6 - #25                 6 - #30     - CAAGTAATGG AATACTAAAA ATGACTAAAA AAGCTTCTAG AAAGCCGAAT TC - #     1974     - (2) INFORMATION FOR SEQ ID NO: 111:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 631 amino               (B) TYPE: amino acid               (D) TOPOLOGY: linear     -     (ii) MOLECULE TYPE: protein     #ID NO: 111:i) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu Leu     Ser     #   15     -      Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser Asn     Pro     #                 30     -      Ser Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Ser Ser Arg     Thr     #             45     -      Lys Ser Asn Leu Lys Lys Leu Ser - # Ile Pro Ser Leu Gly Gly Gly     Met     #         60     -      Lys Leu Val Ala Gln Asn Leu Ser - # Asp Lys Asn Lys Pro Ser Leu     Leu     #     80     -      Asn Glu Asp Asp Tyr Ile Ser Tyr - # Phe Ser Ser Leu Ser Thr Ile     Gln     #   95     -      Asp Asp Val Lys Lys Glu Asn Lys - # Arg His Thr Asn Pro Val Gly     Ser     #                110     -      Ile Asp Glu Pro Asn Ala Thr Asn - # Pro Pro Glu Lys His His Gly     Gln     #            125     -      Arg Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Ile Pro Ser Trp Ser His     Ser     #        140     -      Ser Asn Gly Lys Leu Tyr Leu Gly - # Tyr Tyr Gly Tyr Ala Phe Tyr     Tyr     #    160     -      Gly Asn Lys Thr Ala Thr Asn Leu - # Pro Val Ser Gly Ile Ala Lys     Tyr     #   175     -      Lys Gly Thr Trp Asp Phe Ile Thr - # Ala Thr Lys Asn Gly Gln Arg     Tyr     #                190     -      Ser Leu Phe Gly Ser Ala Phe Gly - # Ala Tyr Asn Arg Arg Ser Ala     Ile     #            205     -      Ser Glu Asp Ile Asp Asn Leu Glu - # Asn Asn Leu Lys Asn Gly Ala     Gly     #        220     -      Leu Thr Ser Glu Phe Thr Val Asn - # Phe Gly Thr Lys Lys Leu Thr     Gly     #    240     -      Lys Leu Tyr Tyr Asn Glu Arg Glu - # Thr Asn Leu Asn Lys Leu Gln     Lys     #   255     -      Arg Lys His Glu Leu Tyr Asp Ile - # Asp Ala Asp Ile Tyr Ser Asn     Arg     #                270     -      Phe Arg Gly Lys Val Lys Pro Thr - # Thr Gln Lys Asp Ser Gln Glu     His     #            285     -      Pro Phe Thr Ser Glu Gly Thr Leu - # Glu Gly Gly Phe Tyr Gly Pro     Asn     #        300     -      Gly Glu Glu Leu Gly Gly Lys Phe - # Leu Ala Gly Asp Asn Arg Val     Phe     #    320     -      Gly Val Phe Ser Ala Lys Glu Glu - # Glu Thr Lys Asp Lys Lys Leu     Ser     #   335     -      Arg Glu Thr Leu Ile Asp Gly Lys - # Leu Ile Thr Phe Lys Arg Thr     Asp     #                350     -      Ala Thr Thr Asn Thr Ala Ala Asn - # Ala Lys Thr Asp Glu Lys Asn     Phe     #            365     -      Thr Thr Lys Asp Ile Pro Ser Phe - # Gly Glu Ala Asp Tyr Leu Leu     Ile     #        380     -      Asp Asn Tyr Pro Val Pro Leu Phe - # Pro Glu Glu Asn Thr Asn Asp     Phe     #    400     -      Ile Thr Ser Arg His His Lys Val - # Gly Asp Lys Thr Tyr Lys Val     Glu     #   415     -      Ala Cys Cys Lys Asn Leu Ser Tyr - # Val Lys Phe Gly Met Tyr Tyr     Glu     #                430     -      Asp Pro Leu Asn Gly Glu Asn Gly - # Lys Glu Lys Glu Lys Glu Lys     Glu     #            445     -      Lys Asp Lys Glu Lys Gln Ala Thr - # Thr Ser Ile Lys Thr Tyr Tyr     Gln     #        460     -      Phe Leu Leu Gly His Arg Thr Ala - # Lys Ala Asp Ile Pro Ala Thr     Gly     #    480     -      Asn Val Lys Tyr Arg Gly Asn Trp - # Phe Gly Tyr Ile Gly Asp Asp     Lys     #   495     -      Thr Ser Tyr Ser Thr Thr Gly Asp - # Lys Asn Ala Val Ala Glu Phe     Asp     #                510     -      Val Asn Phe Ala Asp Lys Thr Leu - # Thr Gly Thr Leu Lys Arg His     Asp     #            525     -      Asn Gly Asn Pro Val Phe Thr Ile - # Asn Ala Ser Phe Gln Ser Gly     Lys     #        540     -      Asn Asp Phe Thr Gly Thr Ala Thr - # Ala Asn Asn Val Ala Ile Asp     Pro     #    560     -      Gln Asn Thr Gln Thr Thr Ser Arg - # Val Asn Phe Thr Ala Thr Val     Asn     #   575     -      Gly Ala Phe Tyr Gly Pro Lys Ala - # Thr Glu Leu Gly Gly Tyr Phe     Thr     #                590     -      Tyr Asn Gly Asn Asn Pro Thr Asp - # Lys Asn Ser Ser Thr Val Ser     Pro     #            605     -      Ser Asn Ser Ala Asn Ala Arg Ala - # Ala Val Val Phe Gly Ala Lys     Lys     #        620     -      Gln Val Glu Thr Thr Asn Lys     #    630     - (2) INFORMATION FOR SEQ ID NO: 112:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 1951 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     -     (ix) FEATURE:               (A) NAME/KEY: CDS               (B) LOCATION: 1..1890     #ID NO: 112:i) SEQUENCE DESCRIPTION: SEQ     - ATG AAA TCT GTA CCT CTT ATC TCT GGT GGA CT - #T TCC CTT TTA TTA AGT       48     Met Lys Ser Val Pro Leu Ile Ser Gly Gly Le - #u Ser Leu Leu Leu Ser     #                 15     - GCT TGT AGC GGG GGA GGT GGT TCT TTT GAT GT - #A GAT GAC GTC TCT AAT       96     Ala Cys Ser Gly Gly Gly Gly Ser Phe Asp Va - #l Asp Asp Val Ser Asn     #             30     - CCC TCC TCT TCT AAA CCA CGT TAT CAA GAC GA - #T ACC TCG AGT CAA AGA      144     Pro Ser Ser Ser Lys Pro Arg Tyr Gln Asp As - #p Thr Ser Ser Gln Arg     #         45     - ACA AAA TCT AAT TTG GAA AAG TTG TCC ATT CC - #T TCT TTA GGA GGA GGG      192     Thr Lys Ser Asn Leu Glu Lys Leu Ser Ile Pr - #o Ser Leu Gly Gly Gly     #     60     - ATG AAA TTG GTG GCT CAG AAT CTG AGT GGT AA - #T AAA GAA CCT AGT TTC      240     Met Lys Leu Val Ala Gln Asn Leu Ser Gly As - #n Lys Glu Pro Ser Phe     # 80     - TTA AAT GGA AAT GAC TAT ATG ATA TTT TCC TC - #A CGT TCT ACG ATT AAA      288     Leu Asn Gly Asn Asp Tyr Met Ile Phe Ser Se - #r Arg Ser Thr Ile Lys     #                 95     - GAT GAT GTT GAA AAT AAC AAT ACA AAC GGG GG - #G GAC TAT ATT GGC TCA      336     Asp Asp Val Glu Asn Asn Asn Thr Asn Gly Gl - #y Asp Tyr Ile Gly Ser     #           110     - ATA GAC GAG CCT AGT ACA ACA AAT CCA CTC GA - #A AAG CAT CAT GGA CAA      384     Ile Asp Glu Pro Ser Thr Thr Asn Pro Leu Gl - #u Lys His His Gly Gln     #       125     - AGG TAT GTA TAT TCA GGG CTT TAT TAT ATT CA - #A TCG TGG AGT CTA AGA      432     Arg Tyr Val Tyr Ser Gly Leu Tyr Tyr Ile Gl - #n Ser Trp Ser Leu Arg     #   140     - GAT TTA CCA AAG AAG TTT TAT TCA GGT TAC TA - #T GGA TAT GCG TAT TAC      480     Asp Leu Pro Lys Lys Phe Tyr Ser Gly Tyr Ty - #r Gly Tyr Ala Tyr Tyr     145                 1 - #50                 1 - #55                 1 -     #60     - TTT GGC AAG GAA ACA GCC ACT ACA TTA CCT GT - #A AAT GGC GAA GCA ACG      528     Phe Gly Lys Glu Thr Ala Thr Thr Leu Pro Va - #l Asn Gly Glu Ala Thr     #               175     - TAT AAA GGA ACT TGG GAT TTC ATC ACT GCA AC - #T AGA AAT GGC AAA AGT      576     Tyr Lys Gly Thr Trp Asp Phe Ile Thr Ala Th - #r Arg Asn Gly Lys Ser     #           190     - TAT TCT TTG TTA AGT AAT AAC CGA CAA GCT TA - #T TCC AAA CGT AGT GCA      624     Tyr Ser Leu Leu Ser Asn Asn Arg Gln Ala Ty - #r Ser Lys Arg Ser Ala     #       205     - ATT CCA GAA GAC ATT GAT TTA GAA AAT GAT CC - #A AAG AAT GGT GAG ACG      672     Ile Pro Glu Asp Ile Asp Leu Glu Asn Asp Pr - #o Lys Asn Gly Glu Thr     #   220     - AGA TTA ACT AGT GAA TTT ACT GTG AAT TTT GG - #T ACG AAA AAG CTC ACA      720     Arg Leu Thr Ser Glu Phe Thr Val Asn Phe Gl - #y Thr Lys Lys Leu Thr     225                 2 - #30                 2 - #35                 2 -     #40     - GGT GGA CTT TAT TAC CAT TTA CGT AAA ACA AA - #T GCT AAT GAA AAC CAA      768     Gly Gly Leu Tyr Tyr His Leu Arg Lys Thr As - #n Ala Asn Glu Asn Gln     #               255     - AAT AGA AAA CAT AAA CTC TAC AAT CTA GAA GC - #T GAT GTG TAT AGC AAC      816     Asn Arg Lys His Lys Leu Tyr Asn Leu Glu Al - #a Asp Val Tyr Ser Asn     #           270     - CGA TTC AGA GGT AAA GTA AAG CCA ACC AAA GA - #G TCT TCT GAA GAA CAT      864     Arg Phe Arg Gly Lys Val Lys Pro Thr Lys Gl - #u Ser Ser Glu Glu His     #       285     - CCC TTT ACC AGC GAG GGA ACA TTA GAA GGT GG - #T TTT TAT GGG CCT AAT      912     Pro Phe Thr Ser Glu Gly Thr Leu Glu Gly Gl - #y Phe Tyr Gly Pro Asn     #   300     - GCT GAA GAA CTA GGG GGA AAA TTT TTA GCT AG - #C GAT AAA AAA GTT TTT      960     Ala Glu Glu Leu Gly Gly Lys Phe Leu Ala Se - #r Asp Lys Lys Val Phe     305                 3 - #10                 3 - #15                 3 -     #20     - GGG GTA TTT AGT GCC AAA GAA CAG CAA GAA AC - #G GAA GAA AAC AAA AAA     1008     Gly Val Phe Ser Ala Lys Glu Gln Gln Glu Th - #r Glu Glu Asn Lys Lys     #               335     - TTA CTC AAA GAA ACC TTA ATT GAT GGC AAG CT - #A ACT ACT TTC TCT ACT     1056     Leu Leu Lys Glu Thr Leu Ile Asp Gly Lys Le - #u Thr Thr Phe Ser Thr     #           350     - AAA AAA ACC AAT GCA ACA ACC GAT GCA ACA AC - #C AGT ACA ACA ACC AGT     1104     Lys Lys Thr Asn Ala Thr Thr Asp Ala Thr Th - #r Ser Thr Thr Thr Ser     #       365     - ACA GCA ACC AAT GCA ACA GCC GAT GCA GAA AA - #C TTT ACG ACA AAA GAT     1152     Thr Ala Thr Asn Ala Thr Ala Asp Ala Glu As - #n Phe Thr Thr Lys Asp     #   380     - ATA TCA AGT TTT GGT GAA GCT GAT TAT CTT TT - #A ATT GAT AAT TAC CCT     1200     Ile Ser Ser Phe Gly Glu Ala Asp Tyr Leu Le - #u Ile Asp Asn Tyr Pro     385                 3 - #90                 3 - #95                 4 -     #00     - GTT CCT CTT TTA CCT GAA AAT ACT AAT GAT TT - #C ATA AGC AGT AAG CAC     1248     Val Pro Leu Leu Pro Glu Asn Thr Asn Asp Ph - #e Ile Ser Ser Lys His     #               415     - CAT GAG GTA GGA GGT AAA CAC TAT AAA GTG GA - #A GCA TGT TGC AAG AAT     1296     His Glu Val Gly Gly Lys His Tyr Lys Val Gl - #u Ala Cys Cys Lys Asn     #           430     - CTA AGC TAT GTG AAA TTT GGT ATA TAT TAT GA - #G GAT AAT GAG AAG AAC     1344     Leu Ser Tyr Val Lys Phe Gly Ile Tyr Tyr Gl - #u Asp Asn Glu Lys Asn     #       445     - ACC AAA ATT GAA ACA GAA CAA TAC CAC CAA TT - #T TTG TTA GGT CTC CGT     1392     Thr Lys Ile Glu Thr Glu Gln Tyr His Gln Ph - #e Leu Leu Gly Leu Arg     #   460     - ACT CCC AGT TCT CAA ATT CCT GCA ACG GGA AA - #C GTG AAA TAT CGC GGT     1440     Thr Pro Ser Ser Gln Ile Pro Ala Thr Gly As - #n Val Lys Tyr Arg Gly     465                 4 - #70                 4 - #75                 4 -     #80     - AGT TGG TTT GGT TAT ATT GGT GAT GAC AAG AC - #A TCT TAC TCC ACT ACT     1488     Ser Trp Phe Gly Tyr Ile Gly Asp Asp Lys Th - #r Ser Tyr Ser Thr Thr     #               495     - GGA GAT AAA AAT GCT CTC GCC GAG TTT GAT GT - #A AAT TTT ACC GAT AAA     1536     Gly Asp Lys Asn Ala Leu Ala Glu Phe Asp Va - #l Asn Phe Thr Asp Lys     #           510     - AAG CTA ACA GGC GAA TTA AAA CGA GCC GAT AA - #T CAA AAT ACC GTA TTT     1584     Lys Leu Thr Gly Glu Leu Lys Arg Ala Asp As - #n Gln Asn Thr Val Phe     #       525     - AGA ATT AAT GCA GAC TTT AAA AAT AAT GAT AA - #T GCC TTC AAA GGT ACA     1632     Arg Ile Asn Ala Asp Phe Lys Asn Asn Asp As - #n Ala Phe Lys Gly Thr     #   540     - GCA ACC GCA GAA AAT TTT GTA ATA GAT GGT AA - #C AAT AGT CAA ACT GGA     1680     Ala Thr Ala Glu Asn Phe Val Ile Asp Gly As - #n Asn Ser Gln Thr Gly     545                 5 - #50                 5 - #55                 5 -     #60     - AAT ACC CAA ATT AAT ATT AAA ACT GAA GTA AA - #T GGG GCA TTT TAT GGT     1728     Asn Thr Gln Ile Asn Ile Lys Thr Glu Val As - #n Gly Ala Phe Tyr Gly     #               575     - CCG AAC GCT ACA GAA TTA GGC GGT TAT TTC AC - #T TAT AAC GGA AAA AAT     1776     Pro Asn Ala Thr Glu Leu Gly Gly Tyr Phe Th - #r Tyr Asn Gly Lys Asn     #           590     - CCT ACA GAT AAA AAT TCT GAA AGT TCC TCA AC - #C GTA CCT TCA CCA CCC     1824     Pro Thr Asp Lys Asn Ser Glu Ser Ser Ser Th - #r Val Pro Ser Pro Pro     #       605     - AAT TCA CCA AAT GCA AGA GCT GCA GTT GTC TT - #T GGT GCT AAA AAA CAA     1872     Asn Ser Pro Asn Ala Arg Ala Ala Val Val Ph - #e Gly Ala Lys Lys Gln     #   620     - GTA GAA AAA AAC AAC AAG TAAAAACAAC CAAGTAATGG AA - #TACTAAAA     1920     Val Glu Lys Asn Asn Lys     625                 6 - #30     #        1951      CTAG AAGCCGAATT C     - (2) INFORMATION FOR SEQ ID NO: 113:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 630 amino               (B) TYPE: amino acid               (D) TOPOLOGY: linear     -     (ii) MOLECULE TYPE: protein     #ID NO: 113:i) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Leu Leu Leu     Ser     #   15     -      Ala Cys Ser Gly Gly Gly Gly Ser - # Phe Asp Val Asp Asp Val Ser     Asn     #                 30     -      Pro Ser Ser Ser Lys Pro Arg Tyr - # Gln Asp Asp Thr Ser Ser Gln     Arg     #             45     -      Thr Lys Ser Asn Leu Glu Lys Leu - # Ser Ile Pro Ser Leu Gly Gly     Gly     #         60     -      Met Lys Leu Val Ala Gln Asn Leu - # Ser Gly Asn Lys Glu Pro Ser     Phe     #     80     -      Leu Asn Gly Asn Asp Tyr Met Ile - # Phe Ser Ser Arg Ser Thr Ile     Lys     #   95     -      Asp Asp Val Glu Asn Asn Asn Thr - # Asn Gly Gly Asp Tyr Ile Gly     Ser     #                110     -      Ile Asp Glu Pro Ser Thr Thr Asn - # Pro Leu Glu Lys His His Gly     Gln     #            125     -      Arg Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Ile Gln Ser Trp Ser Leu     Arg     #        140     -      Asp Leu Pro Lys Lys Phe Tyr Ser - # Gly Tyr Tyr Gly Tyr Ala Tyr     Tyr     #    160     -      Phe Gly Lys Glu Thr Ala Thr Thr - # Leu Pro Val Asn Gly Glu Ala     Thr     #   175     -      Tyr Lys Gly Thr Trp Asp Phe Ile - # Thr Ala Thr Arg Asn Gly Lys     Ser     #                190     -      Tyr Ser Leu Leu Ser Asn Asn Arg - # Gln Ala Tyr Ser Lys Arg Ser     Ala     #            205     -      Ile Pro Glu Asp Ile Asp Leu Glu - # Asn Asp Pro Lys Asn Gly Glu     Thr     #        220     -      Arg Leu Thr Ser Glu Phe Thr Val - # Asn Phe Gly Thr Lys Lys Leu     Thr     #    240     -      Gly Gly Leu Tyr Tyr His Leu Arg - # Lys Thr Asn Ala Asn Glu Asn     Gln     #   255     -      Asn Arg Lys His Lys Leu Tyr Asn - # Leu Glu Ala Asp Val Tyr Ser     Asn     #                270     -      Arg Phe Arg Gly Lys Val Lys Pro - # Thr Lys Glu Ser Ser Glu Glu     His     #            285     -      Pro Phe Thr Ser Glu Gly Thr Leu - # Glu Gly Gly Phe Tyr Gly Pro     Asn     #        300     -      Ala Glu Glu Leu Gly Gly Lys Phe - # Leu Ala Ser Asp Lys Lys Val     Phe     #    320     -      Gly Val Phe Ser Ala Lys Glu Gln - # Gln Glu Thr Glu Glu Asn Lys     Lys     #   335     -      Leu Leu Lys Glu Thr Leu Ile Asp - # Gly Lys Leu Thr Thr Phe Ser     Thr     #                350     -      Lys Lys Thr Asn Ala Thr Thr Asp - # Ala Thr Thr Ser Thr Thr Thr     Ser     #            365     -      Thr Ala Thr Asn Ala Thr Ala Asp - # Ala Glu Asn Phe Thr Thr Lys     Asp     #        380     -      Ile Ser Ser Phe Gly Glu Ala Asp - # Tyr Leu Leu Ile Asp Asn Tyr     Pro     #    400     -      Val Pro Leu Leu Pro Glu Asn Thr - # Asn Asp Phe Ile Ser Ser Lys     His     #   415     -      His Glu Val Gly Gly Lys His Tyr - # Lys Val Glu Ala Cys Cys Lys     Asn     #                430     -      Leu Ser Tyr Val Lys Phe Gly Ile - # Tyr Tyr Glu Asp Asn Glu Lys     Asn     #            445     -      Thr Lys Ile Glu Thr Glu Gln Tyr - # His Gln Phe Leu Leu Gly Leu     Arg     #        460     -      Thr Pro Ser Ser Gln Ile Pro Ala - # Thr Gly Asn Val Lys Tyr Arg     Gly     #    480     -      Ser Trp Phe Gly Tyr Ile Gly Asp - # Asp Lys Thr Ser Tyr Ser Thr     Thr     #   495     -      Gly Asp Lys Asn Ala Leu Ala Glu - # Phe Asp Val Asn Phe Thr Asp     Lys     #                510     -      Lys Leu Thr Gly Glu Leu Lys Arg - # Ala Asp Asn Gln Asn Thr Val     Phe     #            525     -      Arg Ile Asn Ala Asp Phe Lys Asn - # Asn Asp Asn Ala Phe Lys Gly     Thr     #        540     -      Ala Thr Ala Glu Asn Phe Val Ile - # Asp Gly Asn Asn Ser Gln Thr     Gly     #    560     -      Asn Thr Gln Ile Asn Ile Lys Thr - # Glu Val Asn Gly Ala Phe Tyr     Gly     #   575     -      Pro Asn Ala Thr Glu Leu Gly Gly - # Tyr Phe Thr Tyr Asn Gly Lys     Asn     #                590     -      Pro Thr Asp Lys Asn Ser Glu Ser - # Ser Ser Thr Val Pro Ser Pro     Pro     #            605     -      Asn Ser Pro Asn Ala Arg Ala Ala - # Val Val Phe Gly Ala Lys Lys     Gln     #        620     -      Val Glu Lys Asn Asn Lys     #    630     - (2) INFORMATION FOR SEQ ID NO: 114:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 1955 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     -     (ix) FEATURE:               (A) NAME/KEY: CDS               (B) LOCATION: 1..1893     #ID NO: 114:i) SEQUENCE DESCRIPTION: SEQ     - ATG AAA TCT GTA CCT CTT ATC TCT GGT GGA CT - #T TCC TTT TTA CTA AGT       48     Met Lys Ser Val Pro Leu Ile Ser Gly Gly Le - #u Ser Phe Leu Leu Ser     #                 15     - GCT TGT AGC GGA GGG GGG TCT TTT GAT GTA GA - #T AAC GTC TCT AAT ACC       96     Ala Cys Ser Gly Gly Gly Ser Phe Asp Val As - #p Asn Val Ser Asn Thr     #             30     - CCC TCT TCT AAA CCA CGT TAT CAA GAC GAT AC - #C TCG AAT CAA AGA ACA      144     Pro Ser Ser Lys Pro Arg Tyr Gln Asp Asp Th - #r Ser Asn Gln Arg Thr     #         45     - AAA TCT AAA TTG GAA AAG TTG TCC ATT CCT TC - #T TTA GGA GGA GGG ATG      192     Lys Ser Lys Leu Glu Lys Leu Ser Ile Pro Se - #r Leu Gly Gly Gly Met     #     60     - AAG TTA GTT GTG CAA AAT TTT GCT GGT GCT AA - #A GAA CCT AGT TTC TTA      240     Lys Leu Val Val Gln Asn Phe Ala Gly Ala Ly - #s Glu Pro Ser Phe Leu     # 80     - AAT GAA AAT GAC TAT ATA TCA TAT TTT TCC TC - #A CTT TCT ATG ATT AAA      288     Asn Glu Asn Asp Tyr Ile Ser Tyr Phe Ser Se - #r Leu Ser Met Ile Lys     #                 95     - GAT GAT GTT GAA AAT AAC AAT AAA AAT AAG GA - #T ACT CCA ATT GGC TCA      336     Asp Asp Val Glu Asn Asn Asn Lys Asn Lys As - #p Thr Pro Ile Gly Ser     #           110     - ATA GAC GAG CCT AGA GCA CCA AAT TCA AAC GA - #A AAT CAT CAA AAT CAT      384     Ile Asp Glu Pro Arg Ala Pro Asn Ser Asn Gl - #u Asn His Gln Asn His     #       125     - CAT GGA CAG CAA TAT GTA TAT TCG GGT CTT TA - #T TAT ATT CCA TCG TGG      432     His Gly Gln Gln Tyr Val Tyr Ser Gly Leu Ty - #r Tyr Ile Pro Ser Trp     #   140     - CGT CTA ATA AAT TTA CCA AAT AAG TTT TAT TC - #A GGT TAC TAT GGA TAT      480     Arg Leu Ile Asn Leu Pro Asn Lys Phe Tyr Se - #r Gly Tyr Tyr Gly Tyr     145                 1 - #50                 1 - #55                 1 -     #60     - GCG TAT TAC TTT GGC AAG CAA ACT GCC ACT AC - #A TTA CCT GTA AAT GGC      528     Ala Tyr Tyr Phe Gly Lys Gln Thr Ala Thr Th - #r Leu Pro Val Asn Gly     #               175     - GAA GCA ACG TAT AAA GGA ACT TGG AGC TTC AT - #C ACC GCA ACT GAA AGA      576     Glu Ala Thr Tyr Lys Gly Thr Trp Ser Phe Il - #e Thr Ala Thr Glu Arg     #           190     - GGC AAA AAT TAT TCT TTG TTC AAT AAT AGA GG - #T CAA GCT TAT TCT CGA      624     Gly Lys Asn Tyr Ser Leu Phe Asn Asn Arg Gl - #y Gln Ala Tyr Ser Arg     #       205     - CGT AGT GCT ACT CCA GGA GAT ATT GAT TTA GA - #A AAC GGT GAC GCA GGC      672     Arg Ser Ala Thr Pro Gly Asp Ile Asp Leu Gl - #u Asn Gly Asp Ala Gly     #   220     - TTA ACA AGT GAA TTT ACT GTC AAT TTT GGT AC - #A AAA AAG CTC ACT GGA      720     Leu Thr Ser Glu Phe Thr Val Asn Phe Gly Th - #r Lys Lys Leu Thr Gly     225                 2 - #30                 2 - #35                 2 -     #40     - GAA CCT TAT TAT AAT GAA AGG GAA ACA AAT CT - #T AAT CAA TCA AAA GAT      768     Glu Pro Tyr Tyr Asn Glu Arg Glu Thr Asn Le - #u Asn Gln Ser Lys Asp     #               255     - AGA AAA CAT AAA CTC TAC GAT CTA GAA GCT GA - #T GTG TAT AGC AAC CGA      816     Arg Lys His Lys Leu Tyr Asp Leu Glu Ala As - #p Val Tyr Ser Asn Arg     #           270     - TTC AGA GGT ACA GTA AAG CCA ACC AAA AAA GA - #G TCT TCT GAA GAA CAT      864     Phe Arg Gly Thr Val Lys Pro Thr Lys Lys Gl - #u Ser Ser Glu Glu His     #       285     - CCC TTT ACC AGC GAG GGA ACA TTA GAA GGT GG - #T TTT TAT GGG CCT AAT      912     Pro Phe Thr Ser Glu Gly Thr Leu Glu Gly Gl - #y Phe Tyr Gly Pro Asn     #   300     - GCT GAA GAA CTA GGG GGA AAA TTT TTA GCT AG - #C GAT AAA AAA GTT TTT      960     Ala Glu Glu Leu Gly Gly Lys Phe Leu Ala Se - #r Asp Lys Lys Val Phe     305                 3 - #10                 3 - #15                 3 -     #20     - GGG GTA TTT AGT GCC AAA GAA ACG GAA GAA AA - #A CCA AAA TTA CCC AAA     1008     Gly Val Phe Ser Ala Lys Glu Thr Glu Glu Ly - #s Pro Lys Leu Pro Lys     #               335     - GAA ACC TTA ATT GAT GGC AAG CTA ACT ACT TT - #C TCT AAA ACA ACC GAT     1056     Glu Thr Leu Ile Asp Gly Lys Leu Thr Thr Ph - #e Ser Lys Thr Thr Asp     #           350     - ACA ACA ACC AAT AAA ACA ACC AGT GCA AAA AC - #C AAT ACA GAA AAC TTT     1104     Thr Thr Thr Asn Lys Thr Thr Ser Ala Lys Th - #r Asn Thr Glu Asn Phe     #       365     - ACG ACA AAA GAT ATA CCA AGT TTT GGT GAA GC - #T GAT TAT CTT TTA ATT     1152     Thr Thr Lys Asp Ile Pro Ser Phe Gly Glu Al - #a Asp Tyr Leu Leu Ile     #   380     - GAT AAT TAC CCT ATT CCG CTT TTA CCT GAG AG - #T GGT GAT TTC ATA AGT     1200     Asp Asn Tyr Pro Ile Pro Leu Leu Pro Glu Se - #r Gly Asp Phe Ile Ser     385                 3 - #90                 3 - #95                 4 -     #00     - AGT AAG CAC CAT GAG GTA GGA GGT AAA CGC TA - #T AAA GTG GAA GCA TGT     1248     Ser Lys His His Glu Val Gly Gly Lys Arg Ty - #r Lys Val Glu Ala Cys     #               415     - TGC AAG AAT CTA TGC TAT GTG AAA TTT GGT AT - #G TAT TAT GAG GAT AAA     1296     Cys Lys Asn Leu Cys Tyr Val Lys Phe Gly Me - #t Tyr Tyr Glu Asp Lys     #           430     - GAG AAC AAC AAA AAT GAA ACA GAC AAA GAA AA - #A GAA AAA CAA ACG ACA     1344     Glu Asn Asn Lys Asn Glu Thr Asp Lys Glu Ly - #s Glu Lys Gln Thr Thr     #       445     - ACA TCT ATC AAG ACT TAT TAT CAA TTC TTA TT - #A GGT CTC CGG ACT CCC     1392     Thr Ser Ile Lys Thr Tyr Tyr Gln Phe Leu Le - #u Gly Leu Arg Thr Pro     #   460     - AGT TCT GAA ATT CCT AAA ATG GGA AAC GTG AC - #A TAT CGC GGT AGT TGG     1440     Ser Ser Glu Ile Pro Lys Met Gly Asn Val Th - #r Tyr Arg Gly Ser Trp     465                 4 - #70                 4 - #75                 4 -     #80     - TTT GGT TAT ATT GGT GAT GAC AAG ACA TCT TA - #C TCC GCT ACA GGA GAT     1488     Phe Gly Tyr Ile Gly Asp Asp Lys Thr Ser Ty - #r Ser Ala Thr Gly Asp     #               495     - AAA CGA CAA GAT AAA AAT GCT CCC GCC GAG TT - #T AAT GCT GAT TTT AAC     1536     Lys Arg Gln Asp Lys Asn Ala Pro Ala Glu Ph - #e Asn Ala Asp Phe Asn     #           510     - AAT AAA AAG CTA ACA GGC ACA TCA AAA CGA CA - #C GAT AAT CAA AAT CCC     1584     Asn Lys Lys Leu Thr Gly Thr Ser Lys Arg Hi - #s Asp Asn Gln Asn Pro     #       525     - GTG TTT AAC ATT AAG GCA ACC TTT CAA AAT GG - #T CGG AAT GAC TTT GAA     1632     Val Phe Asn Ile Lys Ala Thr Phe Gln Asn Gl - #y Arg Asn Asp Phe Glu     #   540     - GGT ACA GCA ACC GCA GAA AAT TTT GTA ATA GA - #T GGT AAA GAT AGT CAA     1680     Gly Thr Ala Thr Ala Glu Asn Phe Val Ile As - #p Gly Lys Asp Ser Gln     545                 5 - #50                 5 - #55                 5 -     #60     - GGA AAT ACC CCA ATT AAT ATT ACA ACT AAA GT - #A AAC GGG GCA TTT TAT     1728     Gly Asn Thr Pro Ile Asn Ile Thr Thr Lys Va - #l Asn Gly Ala Phe Tyr     #               575     - GGA CCT GAT GCT TCT GAA TTA GGC GGT TAT TT - #C ACC TAT AAC GGA AAA     1776     Gly Pro Asp Ala Ser Glu Leu Gly Gly Tyr Ph - #e Thr Tyr Asn Gly Lys     #           590     - GAC ACT ATA ACT AAA AAT ACT GAA AGT TCC TC - #A ACC GTA CCT TCA CCA     1824     Asp Thr Ile Thr Lys Asn Thr Glu Ser Ser Se - #r Thr Val Pro Ser Pro     #       605     - CCC AAT TCA CCA AAT GCA AGA GCT GCA GTT GT - #G TTT GGA GCT AAA AAA     1872     Pro Asn Ser Pro Asn Ala Arg Ala Ala Val Va - #l Phe Gly Ala Lys Lys     #   620     - CAA GTA GAA ACA ACC AAC AAG TAGAAAAAAA CAAATAATG - #G AATACTAAAA     1923     Gln Val Glu Thr Thr Asn Lys     625                 6 - #30     #        1955      CTAG AAAGCCGAAT TC     - (2) INFORMATION FOR SEQ ID NO: 115:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 631 amino               (B) TYPE: amino acid               (D) TOPOLOGY: linear     -     (ii) MOLECULE TYPE: protein     #ID NO: 115:i) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu Leu     Ser     #   15     -      Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser Asn     Thr     #                 30     -      Pro Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Asn Gln Arg     Thr     #             45     -      Lys Ser Lys Leu Glu Lys Leu Ser - # Ile Pro Ser Leu Gly Gly Gly     Met     #         60     -      Lys Leu Val Val Gln Asn Phe Ala - # Gly Ala Lys Glu Pro Ser Phe     Leu     #     80     -      Asn Glu Asn Asp Tyr Ile Ser Tyr - # Phe Ser Ser Leu Ser Met Ile     Lys     #   95     -      Asp Asp Val Glu Asn Asn Asn Lys - # Asn Lys Asp Thr Pro Ile Gly     Ser     #               110     -      Ile Asp Glu Pro Arg Ala Pro Asn - # Ser Asn Glu Asn His Gln Asn     His     #            125     -      His Gly Gln Gln Tyr Val Tyr Ser - # Gly Leu Tyr Tyr Ile Pro Ser     Trp     #        140     -      Arg Leu Ile Asn Leu Pro Asn Lys - # Phe Tyr Ser Gly Tyr Tyr Gly     Tyr     #    160     -      Ala Tyr Tyr Phe Gly Lys Gln Thr - # Ala Thr Thr Leu Pro Val Asn     Gly     #  175     -      Glu Ala Thr Tyr Lys Gly Thr Trp - # Ser Phe Ile Thr Ala Thr Glu     Arg     #               190     -      Gly Lys Asn Tyr Ser Leu Phe Asn - # Asn Arg Gly Gln Ala Tyr Ser     Arg     #           205     -      Arg Ser Ala Thr Pro Gly Asp Ile - # Asp Leu Glu Asn Gly Asp Ala     Gly     #        220     -      Leu Thr Ser Glu Phe Thr Val Asn - # Phe Gly Thr Lys Lys Leu Thr     Gly     #    240     -      Glu Pro Tyr Tyr Asn Glu Arg Glu - # Thr Asn Leu Asn Gln Ser Lys     Asp     #  255     -      Arg Lys His Lys Leu Tyr Asp Leu - # Glu Ala Asp Val Tyr Ser Asn     Arg     #                270     -      Phe Arg Gly Thr Val Lys Pro Thr - # Lys Lys Glu Ser Ser Glu Glu     His     #            285     -      Pro Phe Thr Ser Glu Gly Thr Leu - # Glu Gly Gly Phe Tyr Gly Pro     Asn     #        300     -      Ala Glu Glu Leu Gly Gly Lys Phe - # Leu Ala Ser Asp Lys Lys Val     Phe     #    320     -      Gly Val Phe Ser Ala Lys Glu Thr - # Glu Glu Lys Pro Lys Leu Pro     Lys     #  335     -      Glu Thr Leu Ile Asp Gly Lys Leu - # Thr Thr Phe Ser Lys Thr Thr     Asp     #               350     -      Thr Thr Thr Asn Lys Thr Thr Ser - # Ala Lys Thr Asn Thr Glu Asn     Phe     #           365     -      Thr Thr Lys Asp Ile Pro Ser Phe - # Gly Glu Ala Asp Tyr Leu Leu     Ile     #        380     -      Asp Asn Tyr Pro Ile Pro Leu Leu - # Pro Glu Ser Gly Asp Phe Ile     Ser     #    400     -      Ser Lys His His Glu Val Gly Gly - # Lys Arg Tyr Lys Val Glu Ala     Cys     #  415     -      Cys Lys Asn Leu Cys Tyr Val Lys - # Phe Gly Met Tyr Tyr Glu Asp     Lys     #                430     -      Glu Asn Asn Lys Asn Glu Thr Asp - # Lys Glu Lys Glu Lys Gln Thr     Thr     #            445     -      Thr Ser Ile Lys Thr Tyr Tyr Gln - # Phe Leu Leu Gly Leu Arg Thr     Pro     #        460     -      Ser Ser Glu Ile Pro Lys Met Gly - # Asn Val Thr Tyr Arg Gly Ser     Trp     #    480     -      Phe Gly Tyr Ile Gly Asp Asp Lys - # Thr Ser Tyr Ser Ala Thr Gly     Asp     #   495     -      Lys Arg Gln Asp Lys Asn Ala Pro - # Ala Glu Phe Asn Ala Asp Phe     Asn     #                510     -      Asn Lys Lys Leu Thr Gly Thr Ser - # Lys Arg His Asp Asn Gln Asn     Pro     #            525     -      Val Phe Asn Ile Lys Ala Thr Phe - # Gln Asn Gly Arg Asn Asp Phe     Glu     #        540     -      Gly Thr Ala Thr Ala Glu Asn Phe - # Val Ile Asp Gly Lys Asp Ser     Gln     #    560     -      Gly Asn Thr Pro Ile Asn Ile Thr - # Thr Lys Val Asn Gly Ala Phe     Tyr     #   575     -      Gly Pro Asp Ala Ser Glu Leu Gly - # Gly Tyr Phe Thr Tyr Asn Gly     Lys     #                590     -      Asp Thr Ile Thr Lys Asn Thr Glu - # Ser Ser Ser Thr Val Pro Ser     Pro     #            605     -      Pro Asn Ser Pro Asn Ala Arg Ala - # Ala Val Val Phe Gly Ala Lys     Lys     #        620     -      Gln Val Glu Thr Thr Asn Lys     #        630     - (2) INFORMATION FOR SEQ ID NO: 116:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 100 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 116:i) SEQUENCE DESCRIPTION: SEQ     - TCTAACTTGA CATTATTACA AAAAAAGATC AATAATGCGA ATTATTATCA AT - #TTTGTATG       60     #   100            AAAT CTGTACCTCT TATCTCTGGT     - (2) INFORMATION FOR SEQ ID NO: 117:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 100 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 117:i) SEQUENCE DESCRIPTION: SEQ     - TCTAACTTGA CATTATTACA AAAAAAGATC AATAATGCGA ATTATTATCA AT - #TTTGTATG       60     #   100            AAAT CTGTACCTCT TATCTCTGGT     - (2) INFORMATION FOR SEQ ID NO: 118:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 99 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 118:i) SEQUENCE DESCRIPTION: SEQ     - TCTAAGTTGA CATTATTACA AAAAAAGAAC AATAATGCGA ATTATTATCA AT - #TTTGTATA       60     #    99            AATC TGTACCTCTT ATCTCTGGT     - (2) INFORMATION FOR SEQ ID NO: 119:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 100 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 119:i) SEQUENCE DESCRIPTION: SEQ     - TCTAAGTTGA CATTATTACA AAAAAAGAAC AATAATGCGA ATTATTATCA AT - #TTTGTATA       60     #   100            AAAT CTGTACCTCT TATCTCTGGT     - (2) INFORMATION FOR SEQ ID NO: 120:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 35 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 120:i) SEQUENCE DESCRIPTION: SEQ     #       35         TGTA CCTCTTATCT CTGGT     - (2) INFORMATION FOR SEQ ID NO: 121:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 61 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 121:i) SEQUENCE DESCRIPTION: SEQ     - GTAGAAACAA CCAAATAATG GAATACTAAA AATGACTAAA AAACCCTATT TT - #CGCCTAAG       60     #               61     - (2) INFORMATION FOR SEQ ID NO: 122:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 61 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 122:i) SEQUENCE DESCRIPTION: SEQ     - GTAGAAACAA CCAAATAATG GAATACTAAA AATGACTAAA AAACCCTATT TT - #CGCCTAAG       60     #               61     - (2) INFORMATION FOR SEQ ID NO: 123:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 61 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 123:i) SEQUENCE DESCRIPTION: SEQ     - GTAGAAACAA CCAAGTAATG GAATACTAAA AATGACTAAA AAACCCTATT TT - #CGCCTAAG       60     #               61     - (2) INFORMATION FOR SEQ ID NO: 124:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 78 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 124:i) SEQUENCE DESCRIPTION: SEQ     - GTAGAAACAA CCAACAAGTA AAAACAACCA AGTAATGGAA TACTAAAAAT GA - #CTAAAAAA       60     #  78              GT     - (2) INFORMATION FOR SEQ ID NO: 125:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 43 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 125:i) SEQUENCE DESCRIPTION: SEQ     # 43               AATG GAATACTAAA AATGACTAAA AAA     - (2) INFORMATION FOR SEQ ID NO: 126:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 60 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 126:i) SEQUENCE DESCRIPTION: SEQ     - GTAGAAACAA CCAACAAGTA AAAACAACCA AGTAATGGAA TACTAAAAAT GA - #CTAAAAAA       60     - (2) INFORMATION FOR SEQ ID NO: 127:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 60 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 127:i) SEQUENCE DESCRIPTION: SEQ     - GTAGAAAAAA ACAACTAGTA AAAACAACCA AGTAATGGAA TACTAAAAAT GA - #CTAAAAAA       60     - (2) INFORMATION FOR SEQ ID NO: 128:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 60 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 128:i) SEQUENCE DESCRIPTION: SEQ     - GTAGAAACAA CCAACAAGTA GAAAAAAACA AATAATGGAA TACTAAAAAT GA - #CTAAAAAA       60     - (2) INFORMATION FOR SEQ ID NO: 129:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 35 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 129:i) SEQUENCE DESCRIPTION: SEQ     #       35         GTCA TTTTTAGTAT TCCAT     - (2) INFORMATION FOR SEQ ID NO: 130:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 58 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 130:i) SEQUENCE DESCRIPTION: SEQ     - TATGTGTTCT GGTGGTGGTT CTTTCGACGT TGACAACGTT TCTAACACTC CC - #TCTTCT       58     - (2) INFORMATION FOR SEQ ID NO: 131:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 59 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 131:i) SEQUENCE DESCRIPTION: SEQ     - ACACAAGACC ACCACCAAGA AAGCTGCAAC TGTTGCAAAG ATTGTGAGGG AG - #AAGATTT       59     - (2) INFORMATION FOR SEQ ID NO: 132:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 9 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 132:i) SEQUENCE DESCRIPTION: SEQ     -      Asn Pro Ala Ser Thr Thr Asn Lys - # Asp     #  5 1     - (2) INFORMATION FOR SEQ ID NO: 133:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 17 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 133:i) SEQUENCE DESCRIPTION: SEQ     -      Asn Pro Ala Ser Thr Thr Ser Leu - # Glu Gly Gly Phe Tyr Gly Pro     Lys     #   15     -      Asp     - (2) INFORMATION FOR SEQ ID NO: 134:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 16 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 134:i) SEQUENCE DESCRIPTION: SEQ     -      Asn Pro Ala Ser Thr Thr Ser Leu - # Glu Gly Gly Phe Tyr Gly Lys     Asp     #   15     - (2) INFORMATION FOR SEQ ID NO: 135:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 16 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 135:i) SEQUENCE DESCRIPTION: SEQ     -      Asn Pro Ala Ser Thr Thr Leu Glu - # Gly Gly Phe Tyr Gly Pro Lys     Asp     #   15     - (2) INFORMATION FOR SEQ ID NO: 136:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 15 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 136:i) SEQUENCE DESCRIPTION: SEQ     -      Asn Pro Ala Ser Thr Thr Leu Glu - # Gly Gly Phe Tyr Gly Lys Asp     #   15     - (2) INFORMATION FOR SEQ ID NO: 137:     -      (i) SEQUENCE CHARACTERISTICS:     #pairs    (A) LENGTH: 35 base               (B) TYPE: nucleic acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 137:i) SEQUENCE DESCRIPTION: SEQ     #       35         GTCA TTTTTAGTAT TCCAT     - (2) INFORMATION FOR SEQ ID NO: 138:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 4 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 138:i) SEQUENCE DESCRIPTION: SEQ     -      Met Thr Lys Lys          1     - (2) INFORMATION FOR SEQ ID NO: 139:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 5 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 139:i) SEQUENCE DESCRIPTION: SEQ     -      Glu Gln Val Leu Asn     #  5 1     - (2) INFORMATION FOR SEQ ID NO: 140:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 9 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 140:i) SEQUENCE DESCRIPTION: SEQ     -      Asp Ile Arg Asp Leu Thr Arg Tyr - # Asp     #  5 1     - (2) INFORMATION FOR SEQ ID NO: 141:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 18 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 141:i) SEQUENCE DESCRIPTION: SEQ     -      Gly Ala Ile Asn Glu Ile Glu Tyr - # Glu Asn Val Lys Ala Val Glu     Ile     #   15     -      Ser Lys     - (2) INFORMATION FOR SEQ ID NO: 142:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 5 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 142:i) SEQUENCE DESCRIPTION: SEQ     -      Val Tyr Asn Leu Phe     #  5 1     - (2) INFORMATION FOR SEQ ID NO: 143:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 9 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 143:i) SEQUENCE DESCRIPTION: SEQ     -      Leu Asn Tyr Arg Tyr Val Thr Trp - # Glu     #  5 1     - (2) INFORMATION FOR SEQ ID NO: 144:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 9 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 144:i) SEQUENCE DESCRIPTION: SEQ     -      Cys Ser Gly Gly Gly Gly Ser Phe - # Asp     #  5 1     - (2) INFORMATION FOR SEQ ID NO: 145:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 9 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 145:i) SEQUENCE DESCRIPTION: SEQ     -      Cys Leu Gly Gly Gly Gly Ser Phe - # Asp     #  5 1     - (2) INFORMATION FOR SEQ ID NO: 146:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 8 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 146:i) SEQUENCE DESCRIPTION: SEQ     -      Leu Ser Gly Gly Phe Phe Gly Pro     #  5 1     - (2) INFORMATION FOR SEQ ID NO: 147:     -      (i) SEQUENCE CHARACTERISTICS:     #acids    (A) LENGTH: 10 amino               (B) TYPE: amino acid               (C) STRANDEDNESS: single               (D) TOPOLOGY: linear     #ID NO: 147:i) SEQUENCE DESCRIPTION: SEQ     -      Met Lys Ser Val Pro Leu Ile Ser - # Gly Ser     #   10     __________________________________________________________________________ 

What we claim is:
 1. An immunogenic composition, comprising at least one active component selected from the group consisting of:(A) a recombinant transferrin receptor protein of Haemophilus influenzae or biologically-functional fragment or analog thereof which retains the immunological properties of the transferrin receptor protein producible in a transformed host containing an expression vector comprising a nucleic acid molecule selected from the group consisting of:(a) a purified and isolated nucleic acid molecule encoding a transferrin receptor protein of a strain of Haemophilus influenzae or a biologically-functional fragment or an analog of the transferrrin receptor protein which retains the immunological properties of the transferrin receptor protein, and (b) a purified and isolated nucleic acid molecule having a DNA sequence selected from the group consisting of:(a) any one of the DNA sequences set of in FIGS. 3A to 3Q, 4A to 4Q, 5A to 5Q, 6A to 6Q, 7A to 7N, 8A to 8G, 9A to 9G, 10A to 10G or 11A to 11G (SEQ ID NOS: 1, 2, 3, 4, 105, 108, 110, 112, 114) or the complementary DNA sequence of any one of said sequences; or (b) a DNA sequence sequence encoding one of the amino acid sequences set out in FIG. 3A to 3Q, 4A to 4Q, 5A to 5Q, 6A to 6Q, 7A to 7N, 8A to 8G, 9A to 9G, 10A to 10G, or 11A to 11G (SEQ ID NOS: 5, 6, 7, 8, 9, 10, 11, 12, 106, 107, 109, 111, 113, 115) or the complementary DNA sequence thereto;and expression means operatively coupled to the nucleic acid molecule for expression by the host of the recombinant transferrin receptor protein or biologically-active fragment or analog thereof which retains the immunological properties of the transferrin receptor protein; (B) an isolated and purified recombinant Tbp1 protein of a strain of Haemophilus influenzae completely free from the Tbp2 protein of the Haemophilus influenzae strain; (C) an isolated and purified recombinant Tbp2 protein of a strain of Haemophilus influenzae completely free from the Tbp1 protein of the Haemophilus influenzae strain; and (D) a synthetic peptide having no less than six amino acids and no more than 150 amino acids and containing an amino acid sequence corresponding to a portion only of a transferrin receptor protein of a strain of Haemophilus influenzae or of a biologically-functional analog of the transferrin receptor protein which retains the immunological properties of the transferrin receptor protein, wherein said transferrin receptor protein has an amino acid sequence which is selected from those presented in FIGS. 3A to 3Q, 4A to 4Q, 5A to 5Q, 6A to 6Q, 7A to 7N, 8A to 8G, 9A to 9G, 10A to 10G, or 11A to 11G (SEQ ID NOS: 5, 6, 7, 8, 9, 10, 11, 12, 106, 107, 109, 111, 113, 115); and a pharmaceutically acceptable carrier therefor, said at least one active component producing an immune response when administered to a host.
 2. The immunogenic composition of claim 1 formulated as a microparticle, capsule or liposome preparation.
 3. The immunogenic composition of claim 1 in combination with a targeting molecule for delivery to specific cells of the immune system or to mucosal surfaces.
 4. The immunogenic composition of claim 1 further comprising an adjuvant. 